DK147854B - METHOD OF ANALOGUE FOR THE PREPARATION OF N- (1-BENZYLPIPERID-4-YL) -BENZAMIDES - Google Patents

Description

147854

The present invention relates to an analogous process for the preparation of N- (1-benzylpiperid-4-yl) -benzamides of the general formula I

X is 2 H 2 N- (O) -CONH- (I> OR 1 ^ R 3 wherein X represents a chlorine or bromine atom, R 4 represents a straight or branched alkyl group of up to 6 carbon atoms, and R 2 represents R or one of these symbols means a chlorine atom at the 3 or 4 position or a methyl or methoxy group at the 4 position, and the other symbol means a hydrogen atom, or R and R taken together represent a methylenedioxy group bonded to 3- and the 4-positions, or ferric cruciferous salts thereof with acids, the compounds of formula I and their salts have, in one of their essential pharmacological properties, the ability to counteract the effects of dopamine or dopaminergic agents of endogenous or exogenous origin. treatment of nausea and vomiting caused by gastrointestinal disorders, debilitating heart function with excessive blood flow, post-operative conditions, other gastrointestinal disorders such as dyspepsia, flatulence, biliary regurgitation, hernia hiatus, gastric ulcer, reflux-oesopha gitis, gastritis, duodenitis and cholelithiasis, and many different conditions affecting the central nervous system, such as acute and chronic psychoses, manic psychosis, schizophrenia, severe behavioral disorders and non-melancholic, depressive conditions and migraines.

Preferred are those compounds of the general formula I wherein X represents a chlorine atom, and more particularly such compounds wherein R 2 represents an ethyl group or - preferably - a methyl group.

ISLAND

group, and especially such compounds wherein R 1 represents a chlorine atom 3 2 3 at the 4-position and R represents a hydrogen atom, or R and R are hydrogen atoms, and their pharmaceutically acceptable acid addition salts, in particular malates, hydrochlorides and methanesulfonates. These preferred compounds include the compound N- (1-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chloro-benzamide, which may also be called 4-amino-N- (1-benzyl-4 -piperidyl) -5-chloro-o-anisamid. This compound has been named "Clebopride" by the World Health Organization.

The process of the invention for the preparation of the N- (1-benzylpiperid-4-yl) benzamides of formula I or pharmaceutically acceptable salts thereof is characterized in that a 2-alkoxy-4-amino-5-halo benzoic acid of the general formula II

X

h2n- {o) -C00H (H) 'i

0RX

wherein X and R1 are as defined above, and whose amino group is optionally protected with an acyl group, or an active derivative of such an acid, is reacted with a 1-benzyl-4-aminopiperidine 3

1478BA

of the general formula III

R 2 (III) R 3 wherein R and R are as defined above and, when the amino group of the compound of formula II or its active derivative is protected, the protective acyl group is removed from the resulting product by hydrolysis, upon which the compound prepared Optionally, the formula I is converted to a pharmaceutically acceptable salt thereof with an acid.

The compounds of formula I are prepared as mentioned by reacting a 2-alkoxy-4-amino-5-halo-benzoic acid of the general formula II, the amino group of which is optionally protected with an acyl group such as acetyl, trifluoroacetyl, chloroacetyl or phthaloyl, or an active derivative of such acid, with a 1-benzyl-4-aminopiperidine of the general formula III and, when the benzoic acid reactant or its active derivative is protected, remove the acyl protecting group from the resulting product by hydrolysis.

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

The reaction is usually carried out in an inert organic solvent such as a halogenated (preferably chlorinated) hydrocarbon, an aromatic hydrocarbon, a C C g g alkyl ester of a C ^g alk alkanoic acid, a ketone or ether having C ^gg alkyl groups or a cyclic ether, e.g. tetrahydrofuran or dioxane, at a temperature of -20 to 150 ° C, depending on the reactants used. When a 2-alkoxy-4-acylamino-5-halo benzoic acid is used, the desired compounds of general formula I are released from the resulting intermediates by acidic hydrolysis of the acyl protecting group in an aqueous or aqueous-alcoholic medium at a temperature between room temperature and 100 ° C. Eg. For example, 2-methoxy-4-acetamido-5-chloro-benzoyl 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 give N- (1-benzylpiperid-4-yl) -2-methoxy-4-acetamido-5-chlorobenzamide, then hydrolyzed in aqueous or aqueous-alcoholic acidic solutions to form N- ( 1-benzylpiperid-4-yl) -2-methoxy--4-amino-5-chlorobenzamide.

When a C- g alk alkyl ester of a 2-methoxy-4-acylamino-5-chlorobenzoic acid is used as a reactant with a 1-benzyl-4-aminopiperidine of formula III, the reaction may be carried out in an inert organic solvent such as an aromatic or chlorinated hydrocarbon, in the presence of a base such as an alkali metal C1-6 alkoxide or an aluminum trialkoxy derivative, with continuous removal of the C1-6 alcohol formed by the reaction.

The 2-alkoxy-4-amino-5-halo benzoic acids of general formula II used as starting compounds for the preparation of compounds of general formula I can be prepared from 4-acetamido-salicylic acid by alkylation and esterification of the 2-hydroxy group and the carboxy group by treatment with a C 1-6 alkyl halide or sulfate in an inert organic solvent, such as a C 1-6 alkyl ester of a C 1-6 alkanoic acid or an alkyl ketone with C 1-6 alkyl groups, in the presence of an inorganic base, such as potassium carbonate. The resulting product is then halogenated at the 5-position of the benzene core with chlorine or bromine in an organic solvent, e.g. acetic acid, in the presence of a heavy metal halide such as ferric chloride. Other halogenating agents, such as iodo-benzene dichloride, may also be used. The corresponding acids can be prepared from the esters obtained by acid hydrolysis in aqueous or aqueous-alcoholic solutions.

The 1-Benzyl-4-aminopiperidines of formula III can be prepared by reducing the corresponding 1-benzyl-piperid-4-one oxymers with an alkali metal aluminum hydride or an alkali metal in an alcoholic solvent (NJ Harper et al., J. Med. Chem 7, 729-732 (1964)).

The 1-Benzyl-piperid-4-one oxymers can be prepared by reacting the corresponding ketones with hydroxylamine hydrochloride in an aqueous-alcoholic solution. The 1-Benzyl-piperid-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 converted to its ethylene ketal with ethylene glycol. The ketal is then reacted with a benzoyl halide to form a 1-benzoyl-piperid-4-one-ethylene ketal which can be reduced with lithium aluminum hydride to form the corresponding 1-benzylpiperide-4-one-ethylene ketal which at acidic hydrolysis gives the 1-benzyl-piperid-4-one.

5 147854

A preferred method of preparing compounds of formula I is the method using a mixed anhydride.

Eg. For example, 2-methoxy-4-amino-5-chlorobenzoic acid can be converted 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 alkyl ester of a C ^g alk alkanoic acid, a ketone or ether having C1gg alkyl groups, a cyclic ether, e.g. tetrahydrofuran or dioxane, at a temperature of -20 ° C to room temperature, and the resulting mixed anhydride can then be reacted with 1-benzyl-4-amino-piperidine to give N- (1-benzylpiperid-4-yl) -2- methoxy-4 - amino-5-chlorobenzamide.

This compound and other compounds of general formula I may also be prepared by condensing the same acid or another acid of general formula II or a 4-acylamino derivative thereof with 1-benzyl-4-aminopiperidine in the presence of a dehydrating agent. such as silicon tetrachloride, a mono-, di- or trialkyl-silyl halide, titanium tetrachloride, Ν, Ν'-dicyclohexylcarbodiimide, thionyl chloride or sulfur trioxide, in dimethylsulfoxide, benzenesulfonyl chloride, p-toluenesulfonylchloride, p-toluenesulfonylchloride The reactions may be carried out in an anhydrous inert organic solvent such as halogenated or aromatic hydrocarbons, pyridine, C ^ ^g alkyl esters of C ^gg alkanoic acids, alkyl ketones or ethers of C ^g alkyl alkyl groups or cyclic ethers, at room temperature and the boiling point of the solvent used. If an acyl protecting group is present, the desired compounds of general formula I are obtained by hydrolysis of the resulting intermediate.

The compounds of general formula I can be converted into pharmaceutically acceptable salts thereof by methods known per se. The salts are formed with biologically and pharmacologically acceptable, inorganic and organic acids. In preparing dosage formulations, one skilled in the art can select the pharmaceutically acceptable salts.

6 14785Å

Of the compounds of this invention, with pharmaceutically acceptable substances, preparations for oral and parenteral administration can be prepared. The pharmaceutically acceptable diluents or carriers which are admixed with the active compound (s) or with salts of such compounds to form such compositions are well known per se, and the compositions may be prepared by methods well known to those skilled in the art.

The compounds of this invention may also be mixed with other active agents against acid and gastric ulcer (with the exception of anti-cholinergic agents) for oral and, where appropriate, parenteral use.

The compounds of this invention have shown effects which may be considered beneficial in the treatment of malfunction of the gastrointestinal system and brain of mammals, including animals and humans. The characteristic properties of these compounds are an antagonism to the effects of the dopaminergic agent, apomorphine, in animals, the local anesthetic effect, and the ability to induce catatonia in rats and mice. As a result, they can be used to treat nausea and vomiting for a variety of reasons and as neuroleptic and sedative agents.

It has been shown that the compounds of this invention have antiemetic and neuroleptic properties and increase the rate of gastric emptying in humans. Eg. For example, compounds of formula I and especially pharmaceutically acceptable salts of "Clebopride" have exhibited such properties at single doses of between 0.01 and 20 mg. They can be used in doses of 0.1-100 mg per day. 24 hours for the treatment of nausea and vomiting caused by gastrointestinal disorders, debilitating heart function with increased blood flow, post-operative conditions, other diseases of the gastrointestinal tract, such as dyspepsia, flatulence, biliary regurgitation, hernia hiatus, gastric ulcer, reflex oesophagitis, reflex oesophagitis, and as an aid in gastrointestinal radiography, or they can be used as neuroleptic or sedative agents. The compounds cause significantly less disruption of the central nervous system than chlorpromazine or other phenothiazine agents with antiemetic effects, probably due to their more selective, anti-dopaminergic effects. Experimental experiments 147854 7 have e.g. shown that the hydrochloride and malate salts of "Clebopride" are extensively metabolized in rats and rabbits. Only very little of the unchanged compound is excreted in the urine. N-Debenzyle ring is a major metabolic reaction. Cleavage of the amide bond does not appear to be a major metabolic reaction. Conjugation with glucuronic acid and / or sulfate occurs extensively in rabbits.

The pharmacokinetics of the agent after intravenous administration follow a similar pattern in both species. The relatively low plasma concentrations observed after oral administration of high doses of the malate salt of "Clebopride" despite the rapidly reaching peak levels indicate good absorption, and the rapid emergence of blood metabolites suggests that extensive, first metabolism and / or uptake takes place in the liver.

The recognition of this phenomenon is important for the evaluation of the pharmacology and toxicology of the agent and for the choice of optimal therapeutic doses for oral and parenteral administration.

Standard pharmacological tests have been conducted with many of the compounds of the general formula in. These experiments have been conducted with rats, mice, dogs and humans.

In many of these experiments, the compounds have been compared to "Metoclopramide" and other known therapeutic compounds having properties similar to those of the compounds of the present invention.

Some of the compounds of this invention have been studied in parallel with "Metoclopramide" for possible antiemetic effects against apomorphine-induced rubbing in rats and as local anesthetics on the rat's nerve (Table I). The most effective compounds have also been studied for their ability to reduce gastric emptying time in rats. It is shown that the first compound (the hydrochloride salt of "Clebopride") has a potency similar to that of "Metoclopramide" in this experiment.

As can be seen from the following Table I, some of these compounds exhibit an action profile similar to the action profile of "Metoclopramide", and in particular the first compound ("Clebopriide" HCl salt) and the second, third and fifth compounds more effective as antiemetic agents. Some of the compounds show no anti-apomorphine effect in rats even at high doses, but antagonize the effect of apomorphine in dogs and pigeons at doses of 10-100 µg / kg and 10-50 mg / kg, respectively.

147854 δ

The compounds cause significantly less central nervous system disruption than chlorpromazine and other phenothiazine agents with antiemetic effects. This is demonstrated in Table III, where it is shown that "Clebopride", like "Metoclopramide" and, unlike chlorpromazine, exhibits an antiemetic effect (anti-apomorphine effect) at doses far from the doses that cause catatonia. The dose of the active compounds in humans can be varied between 0.1 and 100 mg per day. 24 hours in smaller single doses.

The hydrochloride salt of "Clebopride" has been shown to be very effective against apomorphine induced vomiting in dogs. Upon oral administration, the hydrochloride salt has a strength which is approx. 8 times greater than the strength of "Metoclopramide" as shown in Table II.

147854 9 Η ti ο u

-µ <U

id +> + + + + + + + -µ -µ rts o X h «p i — 1 i *

r-i: W

ID QJ +++++ ++ ··

M ti <D

O ίί T3 tP <d ° id 6 Φ ti "d * H β Λ <1) a> m &> μ: <U rl HO +» "Θ · s -µ * w GO Ό + + + + (1) Ο + µ + + + + + "td H -ri +++++ ++ & g +> 03 ++++++ µ µ ti Ό ++++++++>

o <3 Λ 'I M

tw O ·

MH

> 33 fi H <D <d ε i — i ί μ Η Η Η Η H i ® ΛΦ X O U U O U ,, (d ω μ:

Eh i — i 0).

Q) +> Ό +>

G. ISLAND

• H £ -1 Λ µ 03

If I O

i + «a κ a a λ _ σ» σ>

Ci tn, χ λ:> ι ο Αί s \ X +> \ &> ο ί q) 2> g ε • η +> ε

IQ Ή ID LD

C> ιη μ in Ο) · Η »* Η Η +1« Ν VO »·> t Μ Η Π + ¾ td τ) +> ι i> d 0) Ό 0) η = G Φ> Φ g æ η · Η>> η ι -η υ α Β: Λ α) u + u ο ι ηη & >>> CN I "II 2 00 μ: -Η -ri -ri Ρη 2 <! 0 +> +> +> ! ¢ 2 2 Β 'Μ Μ Μ ft ο Ο id id id Ο DS: α Ρ Ρ (d + + + ο (¾ -μ ++ + -ΙΟ ο +> + + + ροπγομρο E-ihd G ++ η aa β and β w κ Cl + Ρί υαυυα 2υ = χ 10 147854

Table II

Protective effects of HCl "Clebopride" salt and "Metochlopramide" against apomorphine induced vomiting in dogs.

EDj-q mg / kg per os

Compound (95% confidence interval) HCl "Clebopride" 43.5 (22.29 - 84.88) "Metoclopramide" 343 (188.04-625.63)

Table III

Antiapomorphine effect, rats Katatoni, rats ED5Qmg / kg p. Os ED50 p * os

Compound 95% confidence interval 95% confidence interval "Clebopride" 1.85 (1.48-2.04) ^ 2 (^ 37} 9 "Metoclopramide" 11.8 (10.58-13.15) 9350179) '70, 34-

Chlorpromazine 7.95 (6.28-10.07) 128236) 18, ° 4 ”

The properties of the compounds of this invention are illustrated by the following discussion of pharmacological study.

It has been shown by pharmacological studies in mice that the HCl "Clebopride" salt is a local anesthetic with a strength somewhat greater than the strength of either "Metoclopramide" or procaine.

Other studies have shown that HCl- "Clebopride" affects the central nervous system. It has e.g. an effect against cramps. "Clebopride" carried a somewhat greater potency than "Metoclopramide" in preventing electrically induced cramps in mice. However, neither "Clebopride" nor "Metoclopramide" appear to inhibit seizures induced by strychnine in mice or have any anti-oxotremorin effect. Nevertheless, both compounds are capable of causing salivation and the tremor in mice that have already been treated with a dose of oxotremorine below the threshold. The HCl "Clebopride" salt, but not "Metoclopramide", inhibits tonic convulsions (anti-leptazole) in mice but apparently does not clonic seizures induced with leptazole.

Both the HCl "Clebopride" salt and "Metoclopramide" inhibit spontaneous motor activity and cause lack of coordination as measured by an accelerating "root rot" in mice.

Catatonia, attributed to "Clebopride", has been observed in rats and to a lesser extent in mice.

The HCl "Clebopride" salt has weak effects on the cardiovascular system and the respiratory system. Eg. induces a slow, intravenous injection of the HCl "Clebopride" salt at a rate of 1 mg / kg / min. in a total amount of 10 mg / kg on cats anesthetized with chloralosis, a slight decrease in both blood pressure and pulse and slows respiratory movements.

HCl- "Clebopride" has no significant effect on the autonomic nervous system.

The HCl "Clebopride" salt has an antipyretic and analgesic effect. Eg. "Clebopride" at an oral dose of 300 mg / kg has an effect similar to the action of 200 mg / kg acetylsalicylic acid against yeast-induced pyresis in rats. "Clebopride" at a dose of 300 mg / kg orally almost completely inhibits the torsional syndrome of mice induced by intraperitoneal injection of acetic acid.

The HCl "Clebopride" salt has a weak anti-inflammatory effect and no significant parasympatholytic effect.

Some of the compounds of this invention, especially the hydrogen chloride, malate and methanesulfonate salts of "Clebopride", have been extensively studied in human trials to determine the maximum dosages and therapeutic effects of the compounds. These compounds have been administered orally and parenterally to humans.

Useful doses of "Clebopride" salts appear to be between 0.1 and 30 mg per day. 24 hours, depending on the length of treatment and the desired therapeutic effect. Such doses of the hydrochloride salt have been found to be practically free of side effects, and single doses of between 0.2 and 5 mg appear to be effective in e.g. an increase in the emptying of the stomach.

A study has been conducted on the effect of "Clebopride" as a means of reducing gastric emptying time in humans using different doses (0.2 mg, 1 mg, 2 mg and 5 mg) compared to 10 mg "Metoclopramide".

All of the compounds are administered orally in liquid suspension, and the patients used had many different diagnoses but some form of stomach disorder in common.

12 147854

The assessment is based on the radiologist's subjective perception of the time before peristaltic waves appear and the ability of these waves to empty the stomach, according to the following scheme: +: no effect ++: moderate effect +++: good effect + +++: maximum impact.

In comparison, 10-20 mg of "Metoclopramide" gives a good effect (+++).

The results obtained with 35 patients are detailed in the following table:

Doses Number of patients + ++ +++ ++++ 0.2 mg 6 006 0 1 mg 6 12 3 0 2 mg 8 0 2 3 3 5 mg 9 0 2 0 7

Control 6 1500

From this and other experiments it has been concluded that 0.2 mg of "Clebopride" provides as fast and powerful a contraction of the stomach as 20 mg of "Metoclopramide". Two mg of "Cle-bopride" works faster and provides a more potent contraction than 20 mg of "Metoclopramide".

Another experiment has been done to investigate the acute tolerance of the malate salt of "Clebopride" after intra-muscular and intravenous administration to humans.

The individuals used were healthy male volunteers between the ages of 20 and 24, and were divided into eight groups and received the investigated compound according to the following schedule:

Group I: 1 mg intramuscularly per day. 24 hours a day.

Group II: 1.5 mg intramuscularly per day. 24 hours a day.

Group III: 2 mg intramuscularly per day. 24 hours a day.

Group IV: 0.25 mg intravenously per 24 hours a day.

Group V: 0.50 mg intravenously per 24 hours a day.

Group VI: 1 mg intravenously per 24 hours a day.

Group VII: 1.5 mg intravenously per 24 hours a day.

Group VIII: 2 mg intravenously per 24 hours a day.

147854 13

The parameters assessed were subjective symptoms, mental disorders, neurological disorders, autonomic symptoms, digestive disorders, urogenital disorders, skin and mucosa, heart rate, blood pressure, temperature, other side effects, blood analysis (leukocytes, hemoglobin content, erythrocyte cholesterol, urea, liver function tests, transaminases), and urine analysis (density, albumin, sediment).

The significant effects are summarized as follows: 1. Among the 4 people in group I, a case of slight sleepiness from the second day of treatment is observed.

2. Fatigue sleepiness and fatigue in three of the four people in group II accompanied by mild depression.

3. Three of the four groups in Group III showed sleepiness, exhaustion and depression followed by euphoria.

4. Sleepiness, fatigue and depression of mean intensity were seen in many patients in groups IV to VIII and did not appear to be dose dependent. In addition, in various cases in groups VII and VIII, some degree of sweating, increased salivation and dryness of the mouth were observed.

5. The blood and urine analysis performed in Groups II and VII showed no significant differences.

Pra DK Patent Application No. 4141/69 and DK Patent No. 124,402 as well as from US Patent No. 3,594,417 are known heterocyclic benzamide compounds which are closely related to and have biological effects as the compounds of Formula I disclosed herein. primarily from these known compounds by containing a benzyl substituent at the nitrogen atom of the piperidine ring, the known compounds having similar structure having a lower alkyl group here.

As can be seen from the comparative test results in Table IV below, wherein the test methods are the ones discussed above, precisely this introduction of a benzyl substituent instead of an alkyl substituent causes a significant increase in biological activity.

147854 14

Table IV Cl h2n- £ V conh -O1 bcH3

Forbin- ^ Antiapomorphine- Lokalanaes. Toxicity, toxicity Rx effect in rats, in mice Ι0ςη in mg / kg minimal effect do- · p.o.

say in mg / kg p.o.

1 CH3> 100 active at 1% / 300 <1000 2 C2H5 25 active at 1%> 300 <1000 3 CH2CgH5 1.56 active at 0.1%> 1000

The following Examples 1-5 illustrate the preparation of various of the compounds of the present invention, and Examples A-j illustrate the preparation of starting compounds and intermediates.

Preparation of Starting Compounds Example A

2-Methoxy-4- (α, α, α-trifluoroacetamido) -5-chlorobenzoic acid 2.65 g (0.037 mol) of chlorine dissolved in 50 ml of acetic acid is slowly added to a suspension of 9 g (0.034 mol) ) 2-Methoxy-4- (α, α, α-trifluoroacetamido) -benzoic acid in 160 ml of acetic acid, keeping the temperature between 15 and 2 ° C.

After the addition, the reaction mixture is kept at room temperature for 4 hours. Then the reaction mixture is poured into ice water to precipitate a white solid which is filtered off and dried. It is then recrystallized from acetone / ether to give 9.1 g of crystals having a melting point of 178-180 ° C (yield: 90%). Similarly, 2-methoxy-4-acetamido-5-chlorobenzoic acid having a melting point of 208-210 ° C is also prepared.

Example B

2-Methoxy-4- (α, α, α-trifluoroacetamido) -5-chlorobenzoyl chloride

A mixture of 10 g (0.033 mol) of 2-methoxy-4- (α, α, α - trifluoroacetamido) -5-chlorobenzoic acid, 6.6 ml of thionyl chloride and 15 ml of dry benzene is heated to 60-70 ° C for 4 hours. . The resulting solution is poured into 50 ml of petroleum ether and the precipitated product is separated by filtration as a colorless solid (9 g), mp 91-93 ° C.

Example C

4-Acetamidosalicylic acid 3 30.6 g (0.2 mole) of p-aminosalicylic acid and 100 cm 2 of ethanol are placed in a 250 ml 1 flask and the mixture is heated to 40 ° C.

20.4 g (0.2 mole) of acetic anhydride is then added at such a rate that the temperature does not exceed 50 ° C. After completion of the addition, the mixture is stirred at 50 ° C for 3 hours.

The product is filtered off. Weight: 36 g, m.p. 235 ° C, yield: 92%.

Example D

Methyl 2-methoxy-4-acetamidobenzoate 34 g (0.17 mol) of 4-acetamidosalicylic acid, 57.96 g (0.42 mol) of potassium carbonate and 250 ml of acetone are placed in a 500 cm3 flask and heated to 40 ° C. Then, maintaining the same temperature, 51.40 g (0.408 mole) of methyl sulfate is added over about 30 minutes. 15 minutes and the mixture is heated under reflux for 5 hours. The mixture is cooled, the potassium sulfate precipitate is filtered off, and the acetone solution is concentrated to 1/3 of its original volume. Dilution with ethyl ether gives a crystalline solid which is filtered off. Weight: 34 g, m.p .: 130-132 ° C, yield: 89%.

EksempelE

16 147854

Methyl 2-methoxy-4-acetamido-5-chlorobenzoate 34.8 g of methyl 2-methoxy-4-acetamidobenzoate, 180 ml of acetic acid 3 and a trace of ferric chloride are placed in a 500 cm flask fitted with a flask. stirrer, a thermometer and a gas line. The solids are dissolved by heating and the solution is cooled to 15 ° C.

While maintaining this temperature, a stream of chlorine is passed through the solution until the weight is increased by 11.2 g, the reaction being controlled by cooling. The resulting solution is poured into 2 liters of water to precipitate a white solid which is filtered off. 33 g of product are obtained, mp 149-152 ° C (yield: 82%).

Example F

2-Methoxy-4-amino-5-chlorobenzoic acid 25.75 g (0.1 mole) of methyl 2-methoxy-4-acetamido-5-chlorobenzoate suspended in 100 ml of ethanol are placed in a 500 ml 3 flask. 40 g of sodium hydroxide dissolved in 150 cm of water are added and the mixture is heated under reflux for 2.5 hours. The mixture is diluted with water and acidified with concentrated hydrochloric acid. The white solid which precipitates is separated and recrystallized from methanol. Weight: 17 g, mp 213-215 ° C, Yield 84%.

Example G · 1-Benzyl-4-piperidone oxime 48 g of 1-benzyl-4-piperidone oxime hydrochloride (1) is 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 ether extraction, 38 g of white solid is obtained. Melting point: 129-131 ° C, yield: 93%. (1) P. Brookers, R. J. Terry and Walker. J. Chem. Soc. 3172 (1957).

Example H. , 17 l <47854 l-Benzyl-4-aminopiperidine 7.6 g (0.2 mol) of lithium aluminum hydride and 300 ml of anhydrous ether are placed in a 1 liter flask equipped with a mechanical stirrer and a Soxhlet extractor. 20 g (0.1 mole) of 1-benzyl-4-piperidone oxime are placed in the Soxhlet insert and the mixture is heated under reflux for 12 hours, after which the excess lithium aluminum hydride is destroyed. The ether extracts are dried and concentrated to dryness to give 18 g of an oil. When distilled in vacuo, 17 g of pure product are obtained, with a boiling point of 103-105 ° C at 0.07 mm Hg.

Similarly, the following compounds are prepared: 1- (p-methoxybenzyl) -4-aminopiperidine dihydrochloride having a melting point of 257-259 ° C, 1- (m-chlorobenzyl) -4-aminopiperidine dihydrochloride having a melting point of 275-276PC and 1- (p-chlorobenzyl) -4-aminopiperidine dihydrochloride having a melting point of 308-310 ° C.

Preparation of End Products Example 1 N- [4 '- (1'-benzyl) -piperidyl] -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-chlorobenzoyl chloride in 100 ml of methyl ethyl ketone is slowly added, keeping the temperature at 0-5 ° C. to a solution of 7.99 g (0.042 mol) of 1-benzyl-4-aminopiperidine in 75 ml of methyl ethyl ketone cooled to a temperature of 0-5 ° C. After the addition is complete, the reaction mixture is kept at the same temperature with stirring for 1 hour and then at room temperature for 5 hours.

The solid precipitated is filtered off, washed with methyl ethyl ketone and then recrystallized from ethanol to give 20 g of a white solid, mp 227-228 ° C, with decomposition.

18 N- [4 '- (1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide hydrochloride 50 ml of 8N sodium hydroxide solution are added to a solution of 15.0 g (0.032 mol) N- [4 '- (1'-benzyl) -piperidyl] -2-methoxy-4- (α, α, α-trifluoroacetamido) -5-chlorobenzamide in 50 ml of ethanol and the reaction mixture is stirred at room temperature for 3 hours. more, after which it is diluted with water and extracted with chloroform. The chloroform extracts are dried, decolorized and concentrated at low temperature to give a residue which is dissolved in acetone. A saturated solution of hydrogen chloride in ethanol is added to the acetone solution until the solution is slightly acidic. The solid is separated and recrystallized from 96% ethanol to give 12.3 g of a white product which is N- [4 '- (1'-benzyl) -piperidyl] -2-methoxyphenyl 4-amino-5-chloro-benzamide hydrochloride hydrate having a melting point of 216-219 ° C.

The free base melts at 193-195 ° C.

Example 2 N- [41- (1'-Benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide

A solution of 15.1 g (0.075 mol) of 2-methoxy-4-amino-5-chloro-benzoic acid in 150 ml of dry tetrahydrofuran is cooled to -15 to -10 ° C.

10.52 ml (0.075 mol) of triethylamine are slowly added in 30 ml of dry tetrahydrofuran and then 7.05 ml (0.075 mol) of ethyl chloroformate, which is also dissolved in dry tetrahydrofuran.

Stir for 1 hour at -15 to -10 ° C and then add 14.26 g (0.075 mol) of 1-benzyl-4-aminopiperidine in 30 ml of tetrahydrofuran. The reaction temperature is allowed to rise to room temperature with stirring and kept at this temperature for 6 hours, after which the precipitate is filtered off. The organic extracts are concentrated at low temperature, the residue is dissolved in chloroform and the solution is washed several times with water.

The chloroform extracts are concentrated at low temperature to form a paste which is dissolved in hot ether and left to crystallize to give 21.2 g of a white solid which is N- [41- (1'-benzyl) - piperidyl] -2-methoxy-4-amino-5-chlorobenzamide having a melting point of 193-195 ° C.

Example 3

N- [4 '- (11-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide (a) 16.5 g (0.081 mol) of 2-methoxy-4-amino-5-chlorobenzoic acid , dissolved in 45o ml of anhydrous tetrahydrofuran, is placed in a 1 liter flask fitted with a stirrer and an extra neck.

11.4 ml (0.081 mol) of triethylamine in 30 ml of tetrahydrofuran are slowly added to this solution, keeping the solution at room temperature. Then the mixture is cooled to between 10 and 0 ° C and 6.48 ml (0.089 mol) of ethyl chloroformate is added in 15 ml of tetrahydrofuran. After stirring for 1 hour at the same temperature, 15.39 g (0.081 mole) of 1-benzyl-4-amino-piperidine dissolved in 30 ml of tetrahydrofuran are added while maintaining the same temperature. After completion of the addition, the mixture is left to stand at between 0 and 10 ° C

for 1 hour and at room temperature for 8 hours. The triethylamine hydrochloride is filtered off and the organic phase is concentrated to dryness to give a white solid which is recrystallized from methanol to give 25.5 g of pure title compound, mp 193-195 ° C (yield: 84% ).

(b) 34.5 g (0.134 mol) of methyl 2-methoxy-4-acetamido-5-chlorobenzoate, 67 ml of xylene, 26.63 g (0.140 mol) of 1-benzyl-4-aminopiperidine and 6.7 g of aluminum isopropylate is placed in a 500 ml flask equipped with a stirrer and a Vigreux distillation column having a height of approx. 30 cm. The mixture is heated until the theoretical amount of methanol is distilled off. The excess xylene is removed and the residue is treated with a mixture of 160 cm 3 of water and 3 40 cm of concentrated hydrochloric acid. The xylene layer is removed and the aqueous solution is basified with sodium hydroxide solution and extracted with chloroform. The chloroform extracts are concentrated and the colorless solid remaining is separated. Melting point: 134-135 ° C.

This solid is heated at reflux with a solution 3 of 134 cm of concentrated hydrochloric acid and 220 cm of water for 1 hour.

The solution is then made basic with sodium hydroxide and then extracted with chloroform. The chloroform extract is concentrated to give the title compound as a white solid, mp 193-195 ° C in 37.5 g (72%) yield.

(C) To a solution of 8.04 g of 2-methoxy-4-amino-5-chlorobenzoic acid and 7.6 g of 4-amino-1-benzylpiperidine in 100 ml of anhydrous pyridine is added 3.4 g of silicon tetrachloride at room temperature. The mixture is then refluxed for 3 hours and the pyridine removed in vacuo. The residue is treated with a mixture of water and chloroform and shaken vigorously to separate an insoluble residue. The clear liquid is decanted off and the aqueous phase is separated and made basic with a solution of sodium carbonate and then extracted with chloroform. The chloroform solution is dried and distilled to give 12 g of the title compound, mp 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 is added 4.1 g of N, N '- dicyclohexylcarbodiimide at room temperature. After a few minutes, 3.8 g of 4-amino-1-benzylpiperidine is added with stirring and the mixture is stirred at room temperature overnight.

The insoluble N, N'-dicyclohexylurea is removed by filtration, the filtrate is washed with water and dried, and the solvent is removed in vacuo. The residue is recrystallized from methanol to give 6.0 g of the title compound, mp 194-195 ° C.

(e) To a solution of 4.90 g of 4-acetamido-5-chloro-2-methoxybenzoic acid in 80 ml of pyridine is added 13 ml of benzenesulfonyl chloride and then 1.9 g of 4-amino-1-benzylpiperidine and the mixture is stirred. at room temperature for 1 hour. It is then poured into ice and water mixture and the product is extracted with chloroform. The chloroform layer is separated, washed with water and dried, and the solvent removed in vacuo. The residue is recrystallized from methanol to give 3.5 g of the 4-acetamido compound, mp 134-135 ° C. This compound is then hydrolyzed by the method described under (b) above to give the pure title compound, mp 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 is added dropwise at a temperature of -5 to 0 ° C. 2.5 g of 2-methoxy-4-acetamido-5-chlorobenzoic acid in 40 ml of anhydrous tetrahydrofuran containing 0.75 ml of triethylamine. After completion of the addition, the mixture is stirred at 0 ° C for 1 hour and then at room temperature for another 1 hour. It is then cooled to -5 to 0 ° C and a solution of 2 g of 4-amino-1-benzylpiperidine in 10 ml of anhydrous tetrahydrofuran is added. The resulting mixture is stirred at 0 ° for 1 hour and at room temperature for 3 hours and the solvent removed in vacuo. To the residue is added 40 ml of water and the resulting solution is basified with sodium hydroxide solution and then extracted with chloroform. The chloroform solutions are separated and dried and the solvent removed. The residue is recrystallized from methanol to give a product having a melting point of 134-135 ° C. This product is hydrolyzed by the method described above under (b) to give the desired compound N- [4 '- (11-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide with a mp 193-195 ° C.

By similar methods the following compounds are prepared: N- [4 '- (1'-p-methoxy-benzyl) -piperidyl] -2-methoxy-4-amino-5-chloro-benzamide hydrochloride having a melting point of 238-239 ° C, N- [41 - (11-m-chlorobenzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide hydrochloride, mp 249-251 ° C, N- [4 '- ( 1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-bromobenzamide hydrochloride having a melting point of 219-221 ° C, N- [41 - (1'-p-chlorobenzyl) -piperidyl] - 2-methoxy-4-amino-5-chloro-benzamide hydrochloride, mp 253-256 ° C.

Example 4 N- [4 '- (1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide fumarate (C20H24ClN3O2, C4H4O4)

A warm solution of 3.75 g of N- [4 '- (1'-benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide in 130 ml of methanol is added to a hot solution of 1.2 g fumaric acid in 60 ml of acetone and 20 ml of methanol.

The resulting solution is filtered and allowed to cool to crystallize 2.7 g of product, mp 209-210 ° C. Similarly, the following salts of Ν- [4 '- (1' - benzyl) -piperidyl] -2-methoxy-4-amino-5-chlorobenzamide are prepared: 22 1 * 7864

Phosphate (C20H24C ^ N3 ° 2'PO4H3 ^ #, #, ........... snip. 224-225 ° C

Succinate ^ 2 (^ 24 ^^ 3 ^^ 4 ^ 6 ^ 4 ^ .................. 166-168 ° C

Citrate Monohydrate ^ 20 ^ 24 ^^ 3 ^^ 61½ ^ ¾ ° ^ ........ 86-90 ° C (s.)

Oxalate (C20 H24 ClN3 O2 C2 H2iV ..................... 234-235 ° C

α-Ketoglutarate (C20H24ClN3O2rC5H6O5) ............. 113-115 ° C

Malate (C20H24ClN3O2fC4H6O5) ...................... 170 ° C (s)

Hydrochloride monohydrate ........................ 217-219 ° C

Claims (3)

147854 Patent Claims. Analogous Process for Preparation of N- (1-Benzylpiperid-4-yl) -benzamides of General Formula I X 2 -C ° NH - <^^ N-CH2- <g ^ (I) OR1 wherein X represents a chlorine or bromine atom, R1 represents a straight or branched alkyl group having up to 6 carbon atoms, and 2 3 R and R represent hydrogen atoms, or one of these symbols means a chlorine atom at the 3 or 4 position, or a methyl or methoxy group at the 4 position, and the other symbol means a hydrogen atom, or R and R together represent a methylenedioxy group attached to the 3- and 4-positions, or pharmaceutically acceptable salts thereof, characterized in that a 2-alkoxy-4-amino-5-halo-benzoic acid of the general formula II x H2-C00H (II) in * wherein X and R 1 is as defined above, and if the amino group is optionally protected with an acyl group, or an active derivative of such an acid, is reacted with a 1-benzyl-4-aminopiperidine of the general formula III H2 - (iii) R 3 23 wherein R and R are as defined above and, when the amino group of the compound of formula II or its active derivative is protected, the protecting acyl group is removed from the resulting product by hydrolysis,