DE2513136C3 - N- (1-Benzylpiperid-4-yl) -benzamides, process for their preparation and pharmaceutical preparations containing them - Google Patents

Description

The invention relates to the subject matter characterized in more detail in the claims.

From DE-OS 21 44 80 pharmaceuticals are known, which contain heterocyclic compounds as active ingredients, among the most general given in their there Definition also includes the claimed benzamides. The previously known pharmaceuticals are said to be used in warm-blooded animals Anti-inflammatory effects, antihypertensive effects on the circulatory system, antihistamine Develop effects and / or sometimes sedative effects on the central nervous system.

The compounds of the invention have as one of their basic pharmacological properties Ability to evaluate the effects of dopamines and dopaminergic agents endogenous and exogenous Counteract origin. They can be used in the treatment of nausea and vomiting as a result of gastrointestinal diseases, heart failure due to rush of blood, after-effects of operations, as well as other gastrointestinal diseases such as indigestion, flatulance, vomiting of bile, Hiatus hernia, gastric ulcer, reflux esophagitis, gastritis, duodenitis and cholelithiasis as well as of various conditions affecting the central nervous system, such as acute and chronic psychiosis, manic psychiosis, schizophrenia, serious behavioral disorders and non-melancholic, depressive Condition and migraines.

Preferred compounds of the invention are those of the general formula I in which X is a chlorine atom means, and in particular those compounds in which Ri is an ethyl or methyl group, and especially compounds in which R2 is a chlorine atom in the 4-position and R3 represent a hydrogen atom, or R2 and R3 are hydrogen atoms, and their pharmaceutically acceptable acid addition salts, such as especially malates, hydrochlorides and methanesulfonates. These preferred compounds include N- (l-Benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide, which is also known as 4-amino-N- (l-benzylpiperid-4-yl) -5-chloro- o-anisamide can be designated. This compound was given the name clebopride by the World Health Organization.

The compounds of the invention are prepared by adding a 2-alkoxy-4-amino-5-halo-benzoic acid of the general formula II

OR]

(wherein X and Rj are as previously defined), their Amino group is optionally protected by an acyl group such as acetyl, trifluoroacetyl, chloroacetyl or Phthaloyl, or an active derivative of such an acid, reacts with a l-benzyl-4-aminopiperidine general formula III

H ₃ N

N-CH ₂

(ΠΙ)

(wherein R _{2 and R 3 are} as previously defined) and, when the amino group of the benzoic acid reactant or its active derivative is protected, the acyl group is removed by subsequent hydrolysis.

As active derivatives of the benzoic acid reactant, esters, acid halides (preferably Chloride), mixed anhydrides, N-imidazolides or azides, or derivatives of N-ethyl-S-phenylisoxazoline-S-sulfonate (Woodwards reagent).

The reaction is usually carried out in an inert organic solvent such as e.g. B. a halogenated (preferably chlorinated) hydrocarbon, an aromatic hydrocarbon, a Ci-C ₆ alkyl ester of a Ci-Ce alkanoic acid,

a Ci-Q-alkyl ketone or ether, or a cyclic ether such as. B. tetrahydrofuran or dioxane; depending on the reactants used, the reaction temperature is between -20 ° and 15O ⁰ C. Using a 2-alkoxy-4-acylamino-5-haIogenbenzoesäure are the compounds of general formula I from the obtained intermediate products by acid hydrolysis of the protective acyl group in aqueous or Aqueous-alcoholic solution at temperatures between normal temperature and 100 ⁰ C released. For example, 2-methoxy-4-acetamido-5-chlorobenzoyl chloride with l-benzyl-4-aminopiperidine in an inert organic solvent in the presence of a tertiary organic base, e.g. B. pyridine or triethylamine, are implemented; this results in N- (1-benzylpiperid-4-yl) -2-methoxy-4-acetamido-5-chlorobenzamide,
which is then hydrolyzed in aqueous or aqueous-alcoholic solution to give N- (l-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide.
If a Ci-C6-alkyl ester of a 2-methoxy-4-acylamino-5-chlorobenzoic acid is reacted as a reactant with a l-benzyl-4-aminopiperidine of the general formula III, the reaction can be carried out in an inert organic solvent such as an aromatic or chlorinated hydrocarbon, be carried out in the presence of a base such as an alkali metal, Ci-C ₆ -AIkOXId or a trialkoxy derivative of aluminum; _{the Ci-C 6} alcohol formed in the reaction is continuously removed.

The 2-alkoxy-4-amino-5-halobenzoic acid of the general Formula II, which serve as starting substances for compounds of general formula I, are off 4-Acetamido-salicylic acid can be prepared by alkylation the 2-hydroxy group and esterification of the carboxy group by treatment with a Ci-Ce alkyl halide or sulfate in an inert organic solvent, such as Ci-Ce alkyl ketone or ester, in Presence of an inorganic base such as sodium carbonate. The resulting product is then in 5-steiung of the benzene nucleus halogenated with chlorine or bromine in an organic solvent such as acetic acid, in the presence of a heavy metal halide such as ferric chloride. Other halogenating agents, such as iodobenzene dichloride, can also be used. The corresponding acids can be formed from the Esters can be obtained by acid hydrolysis in aqueous or aqueous-alcoholic solution.

l-Benzyl-4-aminopiperidine of the general formula III can be prepared by reducing the corresponding l-BenzyI-piperid-4-one oxime with a Alkali metal aluminum hydride or an alkali metal in an alcoholic solution [cf. Harper N.J. et al, J. Med. Chem., 7,729,732 (1964)].

The l-benzyl-piperid-4-one oxime can be shown are made by the reaction of the corresponding ketone with hydroxylamine hydrochloride in aqueous-alcoholic Solution.

The l-Benzylpiperid-4-ones are known according to Process produced [cf. Beckett et al, J. Med. Pharm. Chem., 1, 37 (1959)] or based on 4-piperidone hydrochloride. This is then converted into the ethylene ketal with ethylene glycol the ketal reacted with a benzene halide and thus gives l-benzoylpiperid-4-one ethyl ketal, which is reduced with lithium aluminum hydride to the corresponding l-benzylpiperid-4-one ethylene ketal; the acid hydrolysis gives l-ber.zylpiperid-4-one.

The compounds of the invention are also prepared by reacting a 2-alkoxy-4-aminobenzoic acid of the general formula IV

O V-COOH

OR, >

(IV)

(wherein Ri is as previously defined) or one their active derivatives, e.g. B. a derivative as before with respect to benzoic acid derivatives of the general Formula II was mentioned with a l-benzyl-4-aminopiperidine of the general formula III; by chlorination or brorination of the compound of the general Formula V

(V)

(where Ri, R2 and R3 are as previously defined) a chlorine or bromine atom is introduced into the 5-position of that benzene ring, which with the Carbamoyl group is connected.

According to another embodiment of the invention, the compounds of the general formula I by reacting a benzyl halide of the general formula VII

HaI-CH ₂

(VII)

(wherein R ₂ and R3 are as previously defined, and Hal represents a halogen atom) with an N- (piperid-4-yl) -2-alkoxy-4-amino-5-halobenzamide of the general formula VIII

CONH

Ν --Η (VlH)

OR,

(where X and Ri are as previously defined) manufactured; the primary amino group of this compound is optionally protected by an acyl group, z. B., as mentioned above in relation to the compounds of general formula II. If the Amino group of the benzamide reactant of the general formula VIII is protected, the protective The acyl group of the product obtained was removed by hydrolysis.

The reaction is usually conducted in the presence of an inorganic or organic base in an inert organic solvent The inert organic solvent may be: an aromatic hydrocarbon, a Ci- Ce-alkyl ester of a Ci- Ce- alkanoic acid, a Ci-Ce-alkyl ketone or ether or a

cyclic ethers such as tetrahydrofuran or dioxane, a Ci-C6-alkyl cyanide or a chlorinated hydrocarbon. The reaction takes place at temperatures between ordinary temperature and the boiling point of the • Solvent used. Potassium carbonate or sodium bicarbonate can be used as inorganic bases will.

A preferred method for preparing the compounds of general formula I is the method with mixed anhydrides. For example, 2-methoxy-4-amino-5-chlorobenzoic acid can be mixed with an alkyl chloroformate in the presence of a tertiary base, such as triethylamine or pyridine, in situ into the mixed Anhydride can be converted when in an inert

organic solvents such as a chlorinated hydrocarbon, a Ci-Ce alkyl ester of a Ci-C ₆ fatty acid, a C ₁ -Ce alkyl ketone or ether, a cyclic ether, e.g. B. tetrahydrofuran or dioxane, is carried out at temperatures from -20 ° C to ordinary temperatures; the mixed anhydride can then be reacted with 1-benzyl-4-aminopiperidine to give N- (1-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide. This compound can also be prepared by condensing the same acid or one of its 4-acylamino derivatives with 1-benzyI-4-aminopiperidine in the presence of a dehydrating agent, e.g. B. silicon tetrachloride, mono-, di- or trialkylsilyl halide, titanium tetrachloride, N.N'-dicyclohexylcarbodiimide, thionyl chloride or sulfur trioxide in dimethyl sulfoxide, toluene-p-sulphonyl chloride, acetone dimethyl acetal or a polymeric dehydrating agent. The reactions can be carried out in anhydrous, inert solvents, such as halogenated or aromatic hydrocarbons, pyridine, Q-Co alkyl ketones, esters or ethers, or cyclic ethers at temperatures between normal temperature and the boiling point of the solvent used. If an acyl protecting group is present, the desired compounds of general formula I are prepared by hydrolysis of the resulting intermediates.

The compounds of general formula I can be used in a manner known per se in pharmaceutically acceptable salts are transferred.

The invention therefore also includes salts of compounds of the general formula I with known ones biologically and pharmaceutically acceptable inorganic and organic acids.

The invention also includes pharmaceutical preparations containing a compound according to the general formula I as an active ingredient, in conjunction with pharmaceutically acceptable diluents or carriers. the Mixtures are preferably useful for oral or parenteral administration.

The compounds of the invention have shown effects that are useful for the treatment of gastrointestinal and cerebral disorders in mammals and humans can be considered beneficial. the characteristic properties of these compounds are an antagonism to the effects of the dopaminergic agent apomorphine in animals, a local anesthetic effect, and ability at Induce catatonia in rats and mice. They can therefore be used to treat nausea as well Vomiting of various origins and used as a neuroleptic or sedative Find.

It has been shown to have antiemetic and neuroleptic properties and when Speed up gastric emptying. So have z. B. the compounds of general formula I, and particularly pharmaceutically acceptable salts of clebopride, such properties at single doses shown between 0.01 (10 μg) and 20 mg you can in Doses of 0.1 to 100 mg per day are used in the treatment of nausea and vomiting as a result of gastrointestinal disorders, heart failure through Rush of blood, postoperative conditions, other disorders of the gastrointestinal tract such as dyspepsia, flatulance, Vomiting of bile, hiatus hernia, gastric ulcer, reflex oesophagitis, duodenitis and cholelithiasis, as well as an add-on for X-rays of the gastrointestinal tract or as a neuroleptic agent or Sedatives. The connections cause far less disturbance to the central nervous system than Chlorpromazine or other phenothiazine antiemetics, which is likely to indicate the more antidopaminergic Effect is due. Experimental tests have shown that e.g. B. Hydrochloride and Malates from Clebopride can be largely broken down by rats and rabbits. Very little des

ίο unchanged active substance excreted in the urine. N-debenzylation is the predominant degradation reaction; the splitting of the amide bond evidently plays a role not a big deal. In rabbits, conjugations with glucuronic acid and / or occur to a high degree sulfate.

After intravenous administration, the pharmacokinetics in both animal sores are similar on. Those observed after high oral administration of high doses of the malate of clebopride are relatively low Plasma concentrations rather than a rapidly occurring peak indicate good absorption, and the rapid appearance of the degradation products in the blood suggest that there is extensive degradation in first pass and / or absorption take place in the liver.

This phenomenon is more optimal for pharmacological and toxicological detection and choice therapeutic doses for oral or parenteral administration are important.

Standard pharmacological tests were carried out with many compounds of general formula 1, namely on rats, mice, dogs and humans.

Parallel tests with metoclopramide were carried out with several compounds according to the invention, possible antiemetic effects against apomorphine-induced gnawing in rats and to investigate a local anesthetic effect on the sciatic nerve of rats (see Table I). the most potent compounds were also tested for their ability to reduce gastric emptying time To belittle rats. The clebopride hydrochloride showed a similar effectiveness as that Methoclopramide.

As can be seen in Table I, some of these compounds have a profile of activity similar to that of metoclopramide; In particular, the compounds 1 (HCl salt of cleboprid), 2, 3 and 5 are more effective as antiemetics. Some of the compounds show no anti-apomorphine activity in rats even at high doses, but are effective in dogs and pigeons at doses of 10-100 µg / kg, respectively. 10-50 mg / kg characterized by antagonism to the action of apomorphine.
These compounds cause far less central nervous system disruption than chlorpromazine and other phenothiazine antiemetics. This is evident from Table III, where it is shown that clebopride, like metoclopramide and in contrast to chlorpromazine, exhibits an anti-emetic (anti-apomorphine) effect at doses far from those which cause catatonia. In humans, the dose of the active compounds can be between 0.1 and 100 mg per day in individual divided doses.

The hydrochloride of clebopride has been proven a potent anti-vomiting effect in dogs caused by apomorphine. As Table II shows that when administered orally, the hydrochloride is about 8 times more effective than metoclopramide.

Table I.

ίο

Antiapomorphine
in rats

Local anesthesia (1%)

Catatonia in rats

Cl CH ₃ Cl CH ₃ Cl CH ₃ Cl CH ₃ Cl CH ₃ Metochlopramide Chlorprornazine

H H 4-Cl H 3,4-M ethylene- - dioxy 3-Cl H 4-OCH ₃ H

Antiapomorphin activity in rats established as follows:

+++ effective at 12.5 mg / kg.
++++ effective at 6.25 mg / kg.
+++++ effective at 3.125 mg / kg.

Table II

Protective effect of clebopride hydrochloride and metoclopramide against that caused by apomorphine Vomiting in dogs

link

ED50 | Jg / kg oral
(Confidence limit = 95%)

Clebopride HCl metoclopramide

43.5 (22.29-84.88)
(188.04-625.63)

Table III

link

Antiapomorphin activity in rats ED50 mg / kg orally

(Confidence limit = 95%) catatonia in rats
ED ₅₀ orally

(Confidence limit = 95%)

Clebopride

Metoclopramide

Chlorprornazine

1.85 (1.48-2.04) 11.8 (10.58-13.15) 7.95 (6.28-10.07) 47.58 (79.46-28.37)
93.01 (170.34-50.79)
12.28 (18.04-8.36)

The properties of the compounds of the invention will become more pharmacological through the discussion below Investigations made clear

Pharmacological studies with mice have shown that clebopride hydrochloride is used as a local anesthetic works and is somewhat stronger in its effectiveness than metoclopramide and procaine.

Other research has shown that clebopride hydrochloride affects the central nervous system. B. an antispasmodic effect. Clebopride has a slightly stronger effect than preventing electrically induced convulsions in mice Metoclopramide. However, neither clebopride nor metoclopramide apparently prevent strychnine in mice caused cramps and also has no antioxotremorin effect. However, both compounds are capable of salivating and trembling in mice had previously been treated with a sub-threshold dose of oxotremorine. In contrast to metoclopramine clebopride hydrochloride prevents tonic sugar (antipentetrazole) in mice, but apparently

no clonic caused by pentetrazole

Seizures.

Both clebopride hydrochloride and metoclopramide delay spontaneous motor activity and cause loss of coordination, as could be shown in measurements with the acceleration torsion bar in mice. In rats and Catatonia caused by clebopride has also been found to a lesser extent in mice.

Clebopride hydrochloride has an effect on the cardiovascular and only a weak effect on the respiratory system. So z. B. when anesthetized with a-chloralose Slow intravenous infusion of clebopride hydrochloride into cats at a dose of 1 mg / kg / min and a total dose of 10 mg / kg slight drops in blood pressure and heart rate and slower breathing.

Clebopride hydrochloride has an effect on the autonomic nervous system no noticeable effect.

Clebopride hydrochloride has a distinct antipyretic and analgesic effects. So has z. B. Clebopride at an oral dose of 300 mg / kg against fever caused by yeast in rats, the same effect as 200 mg / kg acetylsalicylic acid. at At an oral dose of 300 mg / kg, clebopride almost completely prevented this in mice intraperitoneal injection of acetic acid induced curvature syndromes.

Clebopride hydrochloride has little anti-inflammatory effect and no noticeable parasympatholytic activity.

Several compounds of the invention, particularly the hydrochloride, malate and methanesulfonate of Clebopride, have been extensively tested in humans, at the maximum doses and the therapeutic ones Determine effectiveness. These compounds have been administered orally and parenterally to humans.

Usable dosages of clebopride appear to be between 0.1 and 30 mg per day, depending on the length the duration of treatment and the desired therapeutic effect. Such dosages of hydrochloride showed no visible side effects and single doses between 0.2 and 5 mg already seem to work act, e.g. B. in accelerating gastric emptying.

A study was conducted to examine the action of clebopride on the shortening of the To clarify gastric emptying time in humans; different doses (0.2, 1, 2 and 5 mg) im Compared to 10 mg metoclopramide applied.

All of the drugs were administered orally as liquid suspensions, and the patients had a variety Diagnoses, however, some gastric disease in common.

The evaluation is based on the subjective opinion of the radiologist by determining the time until the appearance of peristaltic waves and their ability to empty the stomach after following scheme:

+: no effect
+ +: little effect
+ + +: good effect
+ + + +: maximum effect

For orientation: 10-20 mg metoclopramide showed the effect + + +.

The results obtained in 35 patients are summarized in the following table:

dose number ₊ ++ +++ ++++ the mg Patient 0.2 6th 0 0 6th 0 1 6th 1 2 3 0 2 8th 0 2 3 3 5 9 0 2 0 7th control 6th 1 5 0 0

Onset of action and a stronger contraction than 20 mg metoclopramide.

The aim of a further investigation was to determine the acute tolerance of the malate of clebopride after intramuscular and intravenous administration in humans.

The test subjects were healthy, male volunteers between the ages of 20 and 24 years Groups were divided and administered the test compound according to the following schedule:

15th

From this and other experiments it is concluded that 0.2 mg of clebopride causes the stomach to contract just as rapidly and as vigorously as 20 mg of metoclopramide. 2 mg of clebopride result in a faster group I.
Group II
Group III
Group IV
Group v
Group VI
Group VII
Group VIII

1 mg / day, intramuscularly,
For 5 days

1.5 mg / day, intramuscularly,
For 5 days

2 mg / day, intramuscularly,
For 5 days

0.25 mg / day, intravenous,
For 5 days

0.50 mg / day, intravenous,
For 5 days

1 mg / day, intravenous,
For 5 days

1.5 mg / day, intravenous,
For 5 days

2 mg / day, intravenous,
For 5 days

40 The parameters used for the evaluation were subjective symptoms: mental disorders, neurological disorders, autonomic symptoms, digestive disorders, disorders of the urogenital system, skin and mucous membranes, pulse, blood pressure, temperature, other side effects, blood analysis (leukocyte formula, hemoglobin content, erythrocyte sedimentation rate, glucose , Cholesterol, urea, liver function tests, transaminases), urinalysis (density, protein, residue).

The most important effects can be summarized as follows:

1. From the second day of the experiment on, a case of Drowsiness noted.

2. Fatigue, drowsiness and dullness in three of the four test persons in group II, accompanied by mild depression.

3. Three of the four subjects in Group III showed drowsiness, fatigue and depression followed by euphoria.

4. Drowsiness, fatigue and depression mean Intensity were noted in many patients in groups IV to VIII and were apparently independent of the dose. Also in groups VII and VIII were more or less profuse sweats, excessive memory flow and dry mouth observed on various occasions

5. Blood and urine tests showed no significant fluctuations in groups II and VII.

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

50

55

60

example 1

a) 2-Methoxy-4- (oyx ₎ a-trifluoroacetamido) -5-chlorobenzoic acid

2.65 g (0.037 mol) of chlorine, dissolved in 50 ml of acetic acid, became a suspension of 9 g (0.034 mol)

2-Methoxy-4- (a, a, <x-trifluoroacetamido) -benzoic acid in 160 ml of acetic acid were slowly added, the temperature being kept between 15 and 20 ° C.

After the addition was completed, the reaction mixture was left at ordinary temperature for 4 hours ditched. Then the reaction mixture was poured into ice water, leaving a white solid substance precipitated, which was filtered off and dried. It was recrystallized from acetone diethyl ether and yielded 9.1 g Crystals, melting point 178-180 ° C; Yield 90%.

Using the same procedure, but starting from S-methoxy ^ -acetamido-benzoic acid, 2-methoxy ^ -acetamido-S-chlorobenzoic acid was obtained obtain,

Melting point 208 - 210 ° C.

b) 2-methoxy-4- (a, a, a-trifluoroacetamido) -5-chlorobenzoyichloride

A mixture of 10 g (0.033 mol) of 2-methoxy-4- (aA, a-trifluoroacetamido) -5-chlorobenzoic acid, 6.6 ml of thionyl chloride and 15 ml of dry benzene were heated to 60-70 ° C for 4 hours. This solution was in Poured petroleum ether and the precipitated product by filtering off in the form of a colorless, solid substance (9 g) obtained. Melting point 91-93 ° C.

c) N- (I -BenzyIpiperid-4-yl) -2-methoxy-

4- (a, a, a-trifluoroacetamido) -5-chlorobenzarnide-

hydrochloride

A solution of 14.7 g (0.046 mol) of 2-methoxy-4 - («, iXA-trifluoroacetamidoJ-S-chlorobenzoyl chloride in 100 ml of methyl ethyl ketone was slowly and with cooling to a temperature between 0 and 5 ° C. a solution of 7.99 g (0.042 mol) of 1-benzyl-4-aminopiperidine in 75 ml of methyl ethyl ketone, which had been cooled to a temperature of 0-5 ° C. To When the addition was complete, the reaction mixture was kept at this temperature for 1 hour with constant stirring held and then stirred for a further 5 hours at room temperature

The solid substance that had deposited was filtered off, washed with methyl ethyl ketone, from ethanol recrystallized to give, as a white solid substance, 20 g of the desired compound, melting point 227-229 ° C.

d) N- (I -Benzylpiperid-4-yl) -2-emethoxy-
-i-amino-S-chlorobenzamide hydrochloride

50 ml of NaOH (8N) were added to a solution of 15 g (0.032 mol) of N- (1-benzylpiperid-4-yl) -2-methoxy-4- (aAA-trifluoroacetamido) -5-chlorobenzamide in 50 ml of ethanol was added and the reaction mixture was stirred for 3 hours at ordinary temperature. then it was diluted with water and extracted with chloroform The chloroform extracts were dried, decolorized and concentrated at low temperature and the residue obtained thereby dissolved in acetone this solution became a saturated solution of HQ in Ethanol added until the solution was slightly acidic. The solid was separated and after recrystallization from ethanol, 123 g of a white product of the formula N- (1-benzylpiperid-4-yl) -2-methoxy ^ -amino-S-chlorobenzamide hydrochloride were obtained · H2O, melting point 216-219 ° C; the free base had one Melting point of 193-195 ° C.

Example 2
a) = reference example 7

b) N- (I -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 in 150 ml of dry tetrahydrofuran the mixture was cooled to -15 to -10 ° C. 10.5 ml (0.075 mol) triethylamine in 30 ml dry tetrahydrofuran were slowly added and then 7.05 ml (0.075 mol) of ethyl chloroformate, also dissolved in dry tetrahydrofuran.

This mixture was stirred at -15 to -10 ° C. for 1 hour and then 14.26 g (0.075 mol) of 1-benzyI-4-aminopiperidine were added dissolved in 30 ml of tetrahydrofuran was added. The temperature rose while shaking of the reaction mixture to room temperature, at which the mixture was held for an additional 6 hours.

The precipitate was then filtered off. The organic extracts were concentrated at low temperatures, the residue was dissolved in chloroform and the solution was washed several times with water.
The chloroform extracts were concentrated at low temperatures to give a paste which was dissolved in warm diethyl ether and later crystallized therefrom. 21.2 g of a white solid, N- (I -benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide, was obtained. Melting point 193-195 ° C.

Example 3
a) 4- acetamidosalicylic acid

30.6 g (0.2 mol) of p-aminosalicylic acid and 100 cm ³ of ethanol were placed in a 250 ml flask and the mixture heated at 40 C ^c. Then 20.4 g (0.2 mol) of acetic anhydride was added slowly so that the temperature did not reach 50 ⁰ C. After the addition was complete, the mixture was stirred at 50 ° C. for 3 hours. The product was filtered off; Weight 36 g, melting point 235 ° C., yield 92%.

b) methyl 2-methoxy-4-acetamidobenzoate

34 g (0.17 mol) 4-acetamidosalicylic acid, 57.96 g (0.42 mol) K2CO3 and 250 ml acetone were placed in a 500 cm ³ flask and heated to 40 ° C. Then, while maintaining the temperature 51, 40 g (0.408MoI) of methyl sulfate were added within about 15 minutes and the mixture was refluxed for 5 hours. The mixture was cooled, the K2SO4 precipitate was filtered off and the acetone solution was concentrated to V3 of its original volume.After dilution with ethyl ether, a crystalline solid was obtained which was filtered off became; weight

34 g, melting point 130-132 ° C, yield 89%.

cJMethyl ^ -methoxy ^ -acetamido-S-chlorobenzoate

34.8 grams of methyl 2-methoxy-4-acetamidobenzoate

180 ml of acetic acid and a trace of FeCb were placed in a 500 cm ³ flask equipped with a stirrer, a thermometer and a gas inlet tube. The solid substances were dissolved by heating and then the solution was ^{cooled to 15 °} C. While maintaining this temperature, chlorine gas was passed through the solution, the reaction being controlled by cooling until the weight had increased by 11.2 g. The solution was in 2 liters of water

poured and the precipitated, white solid substance filtered off; Weight 33 g, melting point 149-152 ° C, yield 82%.

d) 2-methoxy-4-amino-5-chlorobenzoic acid

25.75 g (0.1 mol) of methyl ^ -methoxy ^ -acetamide-S-chlorobenzoate, suspended in 100 ml of ethanol, were placed in a 500 cm ³ flask. 40 g of NaOH, dissolved in 150 cm ^{3 of} water, were added and the mixture was refluxed for 2.5 hours. The mixture was diluted with water and acidified with concentrated HCl. The precipitated white solid was separated off and recrystallized from methanol; Weight 17 g, melting point 213-215 ° C, yield 84%.

e) l-Benzylpiperid-4-one oxime

48 g of 1-benzylpiperid-4-one oxime hydrochloride [prepared as described by P. Brookers, RJ Terry and Walker, J. Chem, Soc. 3172 (1957)] were filled into a liquid / liquid extraction apparatus and dissolved in a solution of 8 g of MaOH in 100 ml of water. After 7 hours of extraction with diethyl ether, 38 g of a white solid substance were obtained; Melting point 129-131 ⁰ C, yield 93%.

f) l-Ben7.yI-4-aminopiperidine

7.6 g (0.2 mol) of lithium aluminum hydride and 300 ml of anhydrous diethyl ether were placed in a 1 liter flask given, which was equipped with a stirrer and a Soxhlet apparatus. 20 g (0.1 mol) of 1-benzylpiperid-4-one oxime were placed in the Soxhlet cartridge and the mixture was refluxed for 12 hours, after which time the excess of L1AIH4 was destroyed. The ether extracts were dried and evaporated to dryness, yielding 18 g of an oil. To Vacuum distillation gave 17 g of pure product; Boiling point 103-105 ° C at 0.07 mm Hg.

The following compounds were prepared analogously, starting from the corresponding oxime:

l- (p-methoxybenzyl) -4-aminopiperidine,
Melting point of the dihydrochloride 257-259 ⁰ C;
l- (m-chlorobenzyl) -4-aminopiperidine,
Melting point of the dihydrochloride 275-276 ⁰ C;
! - (p-ChlorobenzylH-aminopiperidine,
Melting point of the dihydrochloride 308-310 ⁰ C.

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

16.5 g (0.081 mol) of 2-methoxy-4-amino-5-chlorobenzoic acid (d) dissolved in 450 ml of anhydrous tetrahydrofuran were placed in a 1 liter flask equipped with a stirrer and an additional funnel . 11.4 ml (0.081 mol) of triethylamine in 30 ml of tetrahydrofuran were slowly added to this solution, the solution being kept at room temperature. Then the mixture to 10-O was cooled ⁰ C and 6.48 ml (0.089 mol) of ethyl chloroformate in 15 ml of tetrahydrofuran. After this mixture had been stirred at this temperature for 1 hour, 15.39 g (0.081 mol) of 1-benzyl-4-aminopiperidine (f) dissolved in 30 ml of tetrahydrofuran were added while the temperature was kept constant. After completion of the addition, the mixture was allowed to stand for 1 hour at 0-1O ⁰ C and then a further 8 hours at room temperature. The triethylamine hydrochloride was filtered off and the organic phase was evaporated to dryness, leaving a white solid substance which, after recrystallization from methanol, gave 25.5 g of pure product; Melting point 193-195 ° C, yield 84%.

34.5 g (0.134 mol) of methyl 2-methoxy-4-acetamido-5-chlorobenzoate (c), 67 ml of xylene, 26.63 g (0.140 mol) of 1-benzyl-4-aminopiperidine (f) and 6, 7 g of aluminum isopropoxide were poured into a 500 ml flask which was provided with a stirrer and a distillation column (Vigreux) about 30 cm high. The mixture was heated until the theoretical amount of methanol had passed over. Excess xylene was removed and the residue was ^{treated with a mixture of 160 cm 3 of} water and 40 cm ^{3 of} concentrated HCl. The xylene phase was removed and the aqueous solution made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform extracts were concentrated and the colorless solid that remained was separated off; Melting point 134-135 ° C.

This solid substance was treated under reflux with a solution of 134 cm ^{3 of} concentrated HCl and 220 cm ^{3 of} water for 1 hour. After this time, the solution was made alkaline with sodium hydroxide and extracted with chloroform. The chloroform extract was concentrated and resulted in the desired compound, a white solid; Weight 37.5 g, melting point 193-195 ° C, yield 72%.

To a solution of 8.04 g of 2-methoxy-4-amino-5-chlorobenzoic acid (d) and 7.6 g of l-benzyl-4-aminopiperidine (f) in 100 ml of anhydrous pyridine, 3.4 g of silicon tetrachloride were added at room temperature. The mixture was refluxed for 3 hours and the pyridine removed in vacuo. The residue was treated with a mixture of water and chloroform and shaken vigorously, with a insoluble residue precipitated. The clear liquid was decanted and the aqueous phase separated and made alkaline with a sodium carbonate solution and finally extracted with chloroform. The chloroform solution was dried; 12 g of the desired product were obtained by distillation; Melting point 193-195 ° C.

To a solution of 4.0 g of 2-methoxy-4-amino-5-chlorobenzoic acid (d) in 100 ml of methylene chloride were added 4.1 g of N.N'-dicyclohexylcarbodiimide at room temperature admitted. After a few minutes, 3.8 g of 1-benzyl-4-aminopiperidine (f) were added with stirring and the mixture was stirred at room temperature overnight.

The insoluble Ν, Ν'-dicyclohexylhainstoff was filtered off, the filtrate washed with water, dried and the solvent was distilled off in vacuo. Of the The residue was recrystallized from methanol to give 6.0 g of the desired compound; Melting point: 94-195 ° C.

13 ml were added to a solution of 4.90 g of 4-acetamido-5-chloro-2 · methoxy-benzoic acid in 80 ml of pyridine Benzenesulfonyl chloride and then 1.9 g of 1-benzyl-4-aminopiperidine (f) added and the mixture stirred at room temperature for 1 hour. The mixture was poured into ice water and extracted with chloroform. The chloroform phase was separated off with Washed water, dried and the solvent removed in vacuo. The residue turned off b5 recrystallized methanol and gave 3.5 g of the corresponding 4-actamids; Melting point 134-135 ° C. The hydrolysis of this compound leads to the desired, pure product; Melting point 194-195 ° C.

130 218/163

To a mixture of 2.5 g of N-ethyl-5-phenylisoxazoline-3-sulfonate (Woodward's reagent) in 25 ml of anhydrous acetonitrile, a solution of 2.5 g of 2-methoxy was added dropwise ^{at a temperature of -5 to 0 ° C} -4-acetamido-5-chlorobenzoic acid in 40 ml of anhydrous tetrahydrofuran, which contained 0.75 ml of triethylamine, was added. After the addition had ended, the mixture was ^{stirred for 1 hour at 0} ° C. and then for a further hour at room temperature. It was then cooled to -5 to 0 ^° C. and a solution of 2 g of 1-benzyl-4-aminopiperidine (f) in 10 ml of anhydrous tetrahydrofuran was added. This mixture was stirred for one hour at 0 ° C and then for a further 3 hours at room temperature; then the solvent was removed in vacuo. 40 ml of water was added to the residue, and the resulting solution was made alkaline with a sodium hydroxide solution and then extracted with chloroform. The chloroform solutions were separated off, dried and the solvent removed. The residue was recrystallized from methanol to give a product with a melting point of 134-135 ° C. The hydrolysis of this product led to the desired compound N-il-Benzylpiperid ^ -yr ^ -methoxy ^ -amino-S-chlorobenzamide; Melting point 193-195 "C.

Analogously as described in Example 3, the following compounds - starting from the corresponding starting substances - prepared: N- (l-p-Methoxybenzylpiperid-4-yl) -2-methoxy-

i-amino-S-chlorobenzamide hydrochloride;

Melting point 238-239 ° C;
N- (lm-chlorobenzylpiperid-4-yl) -2-methoxy-

i-amino-S-chlorobenzamide hydrochloride;

Melting point 249-251 ° C;
N- (1-Benzylpiperid-4-yl) -2-methoxy-4-amino-5-bromobenzamide hydrochloride;

Melting point 219-221 ⁰ C;
N- (lp-chlorobenzylpiperid-4-yl) -2-methoxy-

i-amino-S-chlorobenzamide hydrochloride;

Melting point 253 - 256 ° C.

Example 4

N- (l-Benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide fumarate _{(C 2 oH24ClN 3} 02 · C ₄ H ₄ O 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 became a hot solution of 1.2 g of fumaric acid in 60 ml of acetone and 20 ml of methanol admitted. The solution was filtered and the filtrate cooled, whereupon the fumarate of the base crystallized; Yield 2.7 g, melting point 209-210 ° C.

The following salts of N- (1-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide were made analogously manufactured:

10

15th

Phosphate (C ₂₀ H ₂₄ ClN ₃ O ₂ ■ PO ₄ H ₃
Succinate (C ₂₀ H ₂₄ ClN ₃ O ₂ · C ₄ H ₆ O ₄ )
Citrate monohydrate (C ₂₀ H ₂₄ ClN ₃ O ₂ · C ₆ H ₈ O ₇ H ₂ O) Oxalate (C ₂₀ H ₂₄ ClN ₃ O ₂ · C ₂ H ₂ O ₄ )
α-Ketoglutarate (C ₂₀ H _{24 ClN 3} O ₂ · C ₅ H ₆ O ₅ ) Malate (C ₂₀ H ₂₄ ClN ₃ O ₂ · C ₄ H ₆ O ₅ )
Hydrochloride monohydrate melting point 224-225 ° C; Melting point 166-168 ° C; Melting point 86-9O ⁰ C (Z); Melting point 234-235 ⁰ C; Melting point 113-115 ⁰ C; Melting point 170 ^° C. (d); Melting point 217-219 ° C.

Claims (7)

Claims: 1. N- (l-Benzy] piperid-4-yl) -benzamides of the general formula I. I.
H ₂ N - / O \ - C ONH JL - ^CH OR, in which: X is a chlorine or bromine atom, Ri is a straight-chain or branched alkyl group with up to 6 carbon atoms, R ₂ and R _{3 are} hydrogen atoms, or one of these symbols is a chlorine atom in the 3- or 4-position or a methoxy group in the 4-position and the other is a hydrogen atom, or both together are a methylenedioxy group bonded to the 3- and 4-position, and pharmaceutically acceptable salts of these compounds. 2. N- (I -Benzylpiperid ^ -yi ^ -methoxy ^ -amino-S-chlorobenzamide and pharmaceutically acceptable salts thereof. 3. A method for the preparation of the compounds according to claim 1, characterized in that a) that one has a corresponding 2-alkoxy-4-amino-5-halobenzoic acid the general form! Il H ₂ N COOH (U) OR ₁ 15th 20th 35 40 (D Acyl group is protected, or an active derivative of such an acid with a 1-benzyl-4-aminopiperidine of the general formula III N-CH ₂ H ₂ N (wherein R ₂ and R3 are as defined in claim 1) reacted and, if the amino group of the benzoic acid reactant or its active derivative is protected, this acyl protecting group is then removed by hydrolysis; b) that a corresponding 2-alkoxy-4-aminobenzoic acid of the general formula IV H ₂ N COOH (IV) OR, their amino group optionally by one or one of its active derivatives with a 1-Benzyl-4-aminopiperidine of the general formula III converts and the reaction product of the general formula V H ₂ N CONH N-CH ₂ (wherein Ri, R ₂ and R3 are as defined in claim 1) chlorinated or brominated in a manner known per se in order to introduce a chlorine or bromine atom into the 5-position of that benzene ring which is connected to the carbamoyl group; c) that a corresponding benzyl halide of the general formula VII HaI-CH ₂ (vn) 55 60 65 (wherein R ₂ and R _{3 are} as defined in claim 1 and Hal represents a halogen atom) with (V) an N- (piperid-4-yl) -2-alkoxy-4-amino-5-halobenzamide of the general formula VIII H ₂ N CONH ORi Ν —Η (VIII) (where X and Ri are defined as in claim 1 are) whose primary amino group is optionally protected by an acyl group and, when the amino group of the benzamide reactant is protected by the general formula VIII is, this acyl protective group is then removed by hydrolysis. 4. The method of claim 3, feature a), characterized in that the reaction is carried out in an inert organic solvent at temperatures between -20 ° and 150 ⁰ C. 5. The method according to claim 3, feature c), characterized in that the reaction in Presence of an inorganic or organic base in an inert organic solvent is carried out. 6. The method according to claim 3, characterized in that in a subsequent step the so obtained free base of the general formula I converted into a pharmaceutically acceptable salt will. 7. Pharmaceutical preparation, characterized in that it is an active ingredient The compound of claim 1 in association with a pharmaceutically acceptable diluent or carrier.