DE2513136B2 - N- (I -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 the claimed benzamide traps. The previously known pharmaceuticals are said to have anti-inflammatory effects, antihypertensive effects on the circulatory system, anihistaminic effects and / or sometimes sedative effects in warm-blooded animals unfold on the central nervous system.

The compounds of the invention have as one of them basic pharmacological properties the ability to control the effects of dopamines and dopaminergic agents endogenous and exogenous Counteract origin. They can be used in the treatment of wedge and vomiting as a result of gastrointestinal diseases, merz 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 esophagilis, 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, and in particular those compounds in which R 1 is an ethyl or methyl group, and in particular compounds in which R _{2 is} a chlorine atom in the 4-Siellung and Ri represent a hydrogen atom, or R2 and Rj represent hydrogen atoms, as well as their pharmaceutically acceptable acid addition salts, such as in particular malays, hydrochlorides and methanesulfonals. These preferred compounds include

bcnzamid, which is also referred to in another way as 4-amino-N- (l-benzylpipcrid-4-yl) -5-chloro-o-anisamide can be. This compound was given the name Cleboprid 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 H.

H ₂ N

COOH

OR ₁

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

H, N

N-CH ₂

(III)

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

in As active derivatives of the benzoic acid reactant Esters, acid halides (preferably chloride), mixed anhydrides, N-imidazolides or can be used Azides, or derivatives of N-ethyl-S-phenylisoxazoline-S-sulfonate (Woodwards reagent).

r. The reaction will normally take place in an inert organic solvents carried out, such as. B. a halogenated (preferably chlorinated) hydrocarbon, an aromatic hydrocarbon, a Ci-Ce alkyl ester of a Q-CVAIkansäure.

in a Ci-Ce alkyl ketone or ether, or one cyclic ethers such as B. tetrahydrofuran or dioxane; depending on the reactants used, the Reaction temperature between -20 ° and 150 "C. At Use of a 2-alkoxy-4-acylamino-5-halogen

r. benzoic acid 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 freige-

"1" sets. For example, 2-methoxy-4-acetamido-5-chlorobenzoyl chloride and l-benzyl-4-aminopiperidine in one inert organic solvent in the presence of a tertiary organic base, e.g. B. pyridine or triethylamine are reacted; this results in N- (1-benzylpi-

ΊΊ perid-4-yl) -2-methoxy-4-acetamido-5-chlorobenzamide, which is then hydrated in aqueous or aqueous-alcoholic solution to give N- (l-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide. If a Ci — Ce alkyl ester of a 2-methoxy-4-acyl-

Mi amino-5-chlorobenzoic acid as a reactant with a l-Benzyl-4-aminopiperidine of the general formula III is implemented, the reaction can be carried out in an inert organic solvent, such as an aromatic or chlorinated hydrocarbon, in the presence of a

h> base, such as an alkali metal, Ci - CVAIkoxid or a trialkoxy derivative of aluminum; this is the one formed in the reaction Ci - C alcohol removed continuously.

The 2-alkoxy-4-amino-5-halobenzoic acid of the general Formula U, which serve as starting substances for compounds of general formula I, are off 4-Ethamido-salicylic acid can be prepared by alkylation the 2-hydroxy group and esterification of the carboxy group by treatment with a Q-CV alkyl halide or sulfate in an inert organic Solvents, such as Q - Ce alkyl ketone or ester, in Presence of a pure inorganic base such as sodium carbonate. The resulting product is then in the 5-position 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-aniinopiperidine of the general formula III can be prepared by reducing the corresponding l-benzyl-piperid ^ -oncxime 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 1 -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

Method prepared [see Beckett et al, J. Med.

Pharm. Chem, 1, 37 (1959)] or based on

4-piperidone hydrochloride, this is made with ethylene glycol

converted to the ethylene ketal. Then will 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 1-benzylpiperid-4-one-ethyenketal; the

ίο acid hydrolysis gives l-benzylpiperid-4-one.

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

H ₂ N

COOH

(IV)

OR,

(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 2ϊ Formula II was mentioned with a 1-benzyl-4-aminopiperidine of the general formula III; by chlorination or bromination 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 ß; r general formula I by reacting a benzyl halide of the general formula VII

HaI-CH ₂

(VII)

(wherein R2 and R 3 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

II, N

N-H (VIII)

OK,

(where X and Ri are previously defined) made: 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 benzamidecactant of the general formula VIII is protected, then the protective The acyl group of the product obtained was removed by hydrolysis.

The reaction is usually in the presence of an inorganic or organic base in an inert organic solvent carried out. The inert organic solvent can be: an aromatic one Hydrocarbon, a Ci-Ce alkyl ester of a Ci-Q alkanoic acid, a Ci - Q-alkyl ketone or ether or a cyclic ethers such as tetrahydrofuran or Dio;: an, a Ci-Q-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-amho-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 solvent such as a chlorinated one Hydrocarbon, a Ci- CVAIkylester a Ci - CV fatty acid, a Ci-Cb alkyl ketone or -ether, a cyclic ether, e.g. B. tetrahydrofuran or dioxane, working at temperatures from -20 / C up to ordinary temperatures: that mixed anhydride can then be mixed with l-benzyl-4-aniinopiperidine are reacted and gives N- (l-benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzaniide. This bond can also be made by condensing the same acid or one of its 4-acylamino derivatives with l-benzyl-4-aminopiperidine in 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 dimethylsilfoxide, toluene-p-sulphonyl chloride. Acetone dimethylacetal or a polymeric dehydrating agent. The reactions can be carried out in anhydrous, inert ones Solvents such as halogenated or aromatic hydrocarbons, pyridine, Ci-Ce alkyl ketones. Kster or ether, or cyclic ether at temperatures between normal temperature and the boiling point of the solvent used. If an acyl seat group is available. will be the desired Compounds of general formula I prepared by hydrolysis of the intermediate products formed.

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 cha-actcristic properties of these compounds are an antagonism to the effects of the dopaminergic agent apomorphine in animals, a local anesthetic effect, and the ability to induce catatonia in rats and mice. she can therefore be used to treat nausea and vomiting of different origins and as neuroleptic Means or sedatives are used.

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 from 0.1 to 100 mg per day are found in application the treatment of nausea and vomiting as a result of gastrointestinal disorders, heart failure through Rush of blood, postoperative conditions, other disorders of the magea / intestinal canal 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 neuroleptic agents or Sedatives. The connections cause far less disturbance to the central nervous system than Chlorprornazine or other phenothiazine antiemetics. ι what is probably due to 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

excreted in the urine in unchanged active substance. 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

r> sulfate.

After intravenous administration, pharmacokinetics are similar in both animal species on. Those observed after high oral administration of high doses of the malate of clebopride are relatively low

: <> Plasma concentrations instead of a rapidly occurring Peak levels indicate good absorption and the rapid appearance of the breakdown products in the blood suggest that there is extensive breakdown on the first pass and / or uptake in the liver

. '"> take place.

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

> "With many compounds of the general formula I. Standard pharmacological tests were carried out on rats. Mice, dogs and humans.

Parallel tests with metoclopramide were carried out with several compounds according to the invention.

! "> leads to possible antiemetic effects against the Apomorphine-induced gnawing in rats and a local anesthetic effect on the sciatic nerve of rats to be examined (see Table I). The most effective compounds were also on theirs

w Tested for ability to decrease gastric emptying time in rats. The clebopride hydrochloride showed an activity similar to that of metoclopramide.

As can be seen from Table I, show

^J '· some of these compounds on a similar efficacy profile such as metoclopramide: in particular, the compounds 1 (HCI-Saiz of clebopride). 2. 3 and 5 more effective as antiemetics. Some of the compounds show no anti-apomorphine effects even at high doses.

Activity in rats, but in dogs and pigeons at doses of 10-100 μg / kg or 10-50 mg / kg are characterized by an antagonism to the action of apomorphine
These compounds cause far less central nervous system disruption than chlorpromazine and other phenothiazine antiemetics. This is shown in Table III, where it is shown that clebopride, like metoclopramide and in contrast to chlorpromazine, has an antiemetic effect (antiapomorphine agent)

* Kung) shows at doses that are far removed from those cause catatonia. In humans, the dose of the active compounds can range between 0.1 and 100 mg per day in individual divided doses.

The hydrochloride of cleboprid has been proven

*> 5 must have a strong effect against this Apomorphine caused vomiting in dogs. As Table II shows, when administered orally, this is Hydrochloride about 8 times more effective than metoclopramide.

• "'• ι /in R. 25th R, Il 13 136 IO + f Anliapomorphine effect Il + + Table I. CH, H H Local anesthesia katalonic + + X CH, 4-CI Il Anliapomnrphin (1%) for rails CII, 3,4-methylcn- estgesct / l: with rails ; : ί Cl dioxy + + ^: ί! Cl CTI, 3-CI + + + + + k Cl CII, 4-OCII, + + + + Melochlopramide Cl Chlorprom; Cl Rats as follows + + + + + + + + + + + +

+++ effective at 12.5 mg / kg. l- f f f effective at 6.25 mg / kg. t n- r f- effective at 3.125 mg / kg.

Table Il

Educational effects of cleboprid-1 lydrochlnrid and Metoclopramide for vomiting caused by apomorphine in dogs

link

KDso, 'ig / kg orally (Confidences / gren / e 95%)

Clcboprid-IICI
Metoclopramide

43.5 (22.29-84.88) 343 (188.04-625.63)

Table IH

link

Anti-lipomorphine activity in rats EI); m mg / kg orally

(Confidcn / gren / c 95%)

Clebopride

Meitoclopramide

ChloφΓomazin

1.85 (1.48-2.04)

11.8 (10.58-13.15)

7.95 (6.28-10.07)

Catatonia in rats Kl) ^ d oral

(Confidences / gren / e - 95%)

47.58 (79.46-28.37) 93.01 (170.34-50.79) 12.28 (18.04-8.36)

The properties of the compounds according to the invention are illustrated by the following discussion of pharmacological investigations.

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

Other studies have shown that clebopride hydrochloride affects the central nervous system. So it has z. B. an antispasmodic effect. Cleboprid has been used in the prevention of electrically generated Cramps in mice had a slightly stronger effect than metoclopramide. Neither clebopride nor metoclopramide however, apparently prevent cramps caused by strychnine in mice and also have no antioxotremorine effect. Both connections can, however induce salivation and tremors in mice previously administered with a sub-threshold dose of oxotremorine had been treated, in contrast to Metoclopra i (p min prevents clebopride hydrochloride from tonic k-jngen (antipentetrazole) in mice, however, apparently no clonic effects caused by pentetrazole Seizures.

Both clebopride hydrochloride and metoclo-

■> ■> pramid slows down spontaneous motor activity and causes loss of coordination, as could be shown in measurements with the acceleration torsion bar in mice. In rats and to a lesser extent in mice it is also through

ho clebopride induced catatonia has been diagnosed.

Clebopride hydrochloride has only a weak effect on the cardiovascular and respiratory systems Effect. So z. B. with anesthetized with Ä-chloralose Cats a slow intravenous infusion of

b'j clebopride hydrochloride at a dose of 1 mg / kg / min and a total dose of 10 mg / kg a slight decrease in blood pressure and heart rate and a slowdown in breathing.

Cleboprid- Hydrochloric] has an effect on the autonomic nervous system no noticeable effect.

Cleboprid hydrochloride has a marked antipyrctic and analgesic effect. Thus, / .. B. clebopride at an oral dose · on JOO mg / kg versus produced by yeast fever in rats the same effect as 200 mg / kg Acctyisalicylsäure. At a peroral dose of 300 mg / kg, clebopride almost completely prevented the curvature syndrome caused in mice by intraperitoneal injection of acetic acid.

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

Several compounds according to the invention, in particular the hydrochloride, malate and methanesulfonate of Clebopride, have been extensively tested in humans, at the maximum doses and the therapeutic ones To determine effective wedge. 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 the 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 in the ".» compiled in the following table:

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

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

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

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

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 metoclopraniide. 2 mg of clebopride result in a faster group I.
Group Il
Group III
Group IV
Group v
Group Vl
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

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. In the four test subjects in Group I was from the second day of the experiment on, a case of drowsiness was 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 moderate intensity depression have been reported in many of the patients Groups IV to VIII were identified and were apparently dose-independent. In addition, in groups VII and VIII more or less strong sweats, strong storage 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.

example 1

a) 2-Methoxy-4- (a # A-trifluoroacetamido) -5-chlorobenzoic acid

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

Was (\ (\ A-trifluoracetaaiido) -benzoesäurc slowly added in 160 ml of acetic acid, wherein the temperature between 15 and 20 ^0C held - 2-Metlioxy-fourth

After the addition was complete, 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 to give 9.1 g Crystals, m.p. 178-180 "C; yield 90%.

Using the same procedure, but starting from 2-methoxy-4-acetamido-benzoic acid. became 2-methoxy-4-ecetamido-5-chlorobenzoic acid received,

Melting point 208-210 ° C.

b) 2-methoxy-4- (Ä, «,« - trifluoroacetamido) -5-chlorobenzoyl chloride

LlMC iriiäCüÜMg 5U3 lug ^ u ₁ UJJ mGiy z-iviCiltOXy-r-

(aAA-trifluoroacetamido) -5-chlorobenzoic acid, 6.6 ml Thionyl chloride and 15 ml of dry benzene was 4 Heated to 60-70 ° C for 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- (1 -Benzylpiperid-4-yl) -2-methoxy-

4- (xflt, ft-trifluoroacetami. ' ^L o) -5-chlorobenzarnide-

hydrochloride

A solution of 14.7 g (0.046 mol) of 2-methoxy-4- (iXAA-trifluoroacetamidoJ-S-chlorobenzoyl chloride in 100 ml of methyl ethyl ketone was added 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- (1-Benzylpiperid-4-yl) -2-emethoxy-4-amino-5-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- (ot ^ t / x-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. to a saturated solution of HCl in ethanol was added to this solution until the solution was weakly acidic. The solid was separated off and, after recrystallization from ethanol, 123 g of a white one were obtained Product of the formula N- (1-benzylpiperid-4-yl) -2-methoxy-'r-arnino-S-chlorobenzarnide hydrochloride · 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 was cooled to -15 to -10 ⁰ C. 10.5 nil

κι (0.075 mol) of triethylamine in 30 ml of dry tetrahydrofuran were slowly added and then 7.05 ml (0.075 mol) of ethyl chloroformate. also dissolved in dry tetrahydrofuran.
This mixture was at -15 to -10 ^c CI hour

ι '. stirred and then 14.26 g (0.075 mol) of I-benzyl-4-eminopiperidine dissolved in 30 ml of tetrahydrofuran were added. With shaking, the temperature of the reaction mixture adjusted to room temperature, at uCr uic miSCiiÜMg ιιΊΓ 'vVciicTc υ J (UnUCM gcuaitcM * νΥϋΐ \ ιΟ.

? <"Then the precipitate was 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 used at low temperatures

2i temperatures and resulted in a paste that in was dissolved in warm diethyl ether and later crystallized from it. 21.2 g of a white solid substance, N- (l-Benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzamide, were obtained, melting point

193-195 ° C.

Example 3
a) 4-acetamidosalicylic acid

s ") 30.6 g (0.2 mol) of p-aminosalicylic acid and ³ lOOcni ethanol were placed in a 250 ml flask and the mixture to 40" C heated. Then 20.4 g (0.2 mol) of acetic anhydride were added so slowly that the temperature did not reach 50.degree. To

At 4M completion of the addition, the mixture was left for 3 hours stirred at 50 ° C. The product was filtered off; Weight 36 g, melting point 235 ° C. Yield 92%.

b) methyl-2-methoxy-4-acetamidobero /> at

4> 34 g (0,? 7 mol) of 4-Acetamidoselicylsäure, 57.96 g (0.42 mol) of K ₂ CO ₃ and 250 ml of acetone was added ³ flask to a 500 cm and heated to 4O ⁰ C. Then, while maintaining the temperature, 51.40 g (0.408 mol) of methyl sulfate were within about 15

"i" added minutes and the mixture under for 5 hours Heated to reflux. The mixture was cooled, the K2SO <precipitate was filtered off and the acetone solution narrowed to 1/3 of its original volume. To Dilution with ethyl ether gave a crystalline solid which was filtered off; weight 34 g. Melting point 130-132 ° C, yield 89%.

cJMethyl ^ -methoxy ^ -acetamido-S-chlorobenzoate

34.8 g of methyl 2-methoxy-4-acetamidobenzoate,

180 ml of acetic acid and a trace of FeCU 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 bubbled through the solution, the reaction being controlled by cooling until the weight 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 2-methoxy-4-acetamido-5-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-oxün

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

f) 1-Benzyl-4-aminopiperidine

7.6 g (0.2 mole) lithium aluminum hydride and 300 ml anhydrous diethyl ether was placed in a 1 liter flask equipped with a stirrer and a Soxhlet apparatus. 20 g (0.1 mol) of l-BenzyIpiperid-4-one oxime were filled into the Soxhlet cartridge and the The mixture was heated under reflux for 12 hours, after which the excess UAIH4 was destroyed. The ether extracts were dried and dried to dryness evaporated, resulting in 18 g of a UI. 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:

1 - (p-Methüxybenzyl) -4-aminopiperidin, melting point of the dihydrochloride 257-259 ⁰ C; 1 - <m-chlorobenzyl) -4-aminopiperidine, melting point of the dihydrochloride 275-276 ° C; 1 - (p-Chlorobenzyl) -4-aminopiperidine, melting point of the dihydrochloride 308-310 ° C.

N- (1 -Benzylpiperid-4-yl) -2-methoxy-4-amino-5-chlorobenzam * d

163 g (0.081 mol) of 2-methoxy-4-amino-5-chlorobenzoic acid (d) dissolved in 450 ml of anhydrous tetrahydrofuran was placed in a 1 liter flask fitted with a stirrer and an additional funnel. To this solution, 11.4 ml (0.081 mol) of triethylamine in 30 ml of tetrahydrofuran was slowly added, the solution being kept at room temperature. Then, the mixture was cooled to 10-0 ⁰ C and 6.48 ml (0.089 mol) Ätliylchloroformat added in 15 ml of tetrahydrofuran. After this mixture had been stirred at this temperature for 1 hour _f 15.39 g (0.081 mol) of J-benzyl-4-aminopiperidine (f) were added dissolved in 30 ml of tetrahydrofuran, the temperature being still kept constant. After completion of the addition, the mixture was allowed to stand for 1 hour at 0-10 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, whereby a lingering solid remained which, after recrystallization from methanol, yielded 25.5 g of pure product; Melting point 193-195 ° e, yield 84%. 34.5 g (0.134MoI) MetbyW-metboxy- ^ l-acetamido-S- chlorobenzoate (c), 67 ml xylene, 26.63 g (0.14OMol) 1-Benzyl-4-aminapiperidine (f) and 6.7 g of aluminum isopropoxide were placed in a 500 ml flask containing was provided with a stirrer and a distillation column (Vigreux) of about 30 cm in height. the The mixture was heated until the theoretical amount of methanol had passed over. Excess xylene was removed and the residue ^{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 with sodium hydroxide solution alkaline made and extracted with chloroform. The chloroform extracts were concentrated and the remaining colorless solid 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 extracted concentrated and resulted in the desired compound, a white solid; Weight 37.5 g, mp 193- 195 ⁰ C, yield 72%.

To a solution of 8.04 g of 2-methoxy-4-amino-5-chlorobenzoic acid (d) and 7.6 g of i-benzyl-4-aminopiperi- din (f) in 100 ml of anhydrous pyridine were added 3.4 g of silicon tetrachloride at room temperature. The mixture was refluxed for 3 hours and the pyridine removed in vacuo. The residue was made with a mixture of water and chloroform treated and shaken vigorously, taking 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.

ό solution was dried; by distillation 12 g of the desired product are obtained; 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'-dicydohexylcarbodiimide were added at room temperature. After a few minutes they were under Stirring added 33 g of 1-benzyl-4-aminopiperidine (f) and the mixture was stirred at room temperature overnight

The insoluble N, N'-dicyck> hexylurea was filtered off, the filtrate washed with water, dried and the solvent is distilled off in vacuo. The residue was recrystallized from methanol and gave 6.0 g of the desired compound; Enamel point 94-195 ^e 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 l-benzyl-4-aminopiperidine (f) are added and the mixture is added Room temperature stirred for 1 hour The mixture was poured into ice water and treated with chloroform extracted. The chloroform phase was separated off, washed with water, dried and the solvent peeled off in vacuo. The residue turned off

<n methanol recrystallized and gave 3.5 g of the corresponding 4-actamide; Melting point 134-135 ⁰ C. The hydrolysis of this compound leading to the desired, pure product; Melting point 194-195 ⁰ C.

030 126/202

To a mixture of 2β g ff-y
zolm-3-sulfonate (Woodward! »reagent) to 25 ml of anhydrous acetonitrile was at a temperature of -5 to 0 ⁰ C dropwise a solution of 2 g of 2-methoxy-4-acetamido-5-chlorobenzoic acid in 40 ml of anhydrous tetrahydrofuran added, 0.75 ml of triethylamine After completion of the addition, the mixture was stirred for 1 hour at 0 ⁰ C and then at room temperature for a further hour, then was cooled to -5 to 0 ° C and a solution of 2 g l -Benzyl-4-aminopiperidine (f) in 10 ml of anhydrous tetrahydrofuran was added. This mixture was stirred for one hour at 0 ° C and then an additional 3 hours at room temperature; thereafter the solvent was removed in vacuo. The residue was added 40 ml of water and the resulting solution was made alkaline with a sodium hydroxide solution and then extracted with chloroform. The chloroform solutions were separated, dried and the solvent removed. The residue was recrystallized from methanol to give a product containing the Melting point 134-135 ° C. Hydrolysis of this product led to the desired compound N- (1 -benzylpiperid ^ ylJ ^ -methoxy ^ amino-S-chlorobenzamide; melting point 193-195 ° C

Analogously as described in Example 3, the following compounds - starting from the corresponding starting substances - produced:

N- (J-p-methoxybenzylpiperjd-4-yl) -2-metboxy-

^ amino'S-ßhjorbenzamide hydrochloride;

Melting point 238-239 ° C; N-il-m-CblorbenzyJpiperid- ^ yl ^ -methoxy »

^ amino-S-chlorobenzamide hydrochloride;

Melting point 249-251 ⁰ C; N- (t-Benzylpjperid-4-yl) -2-methoxy- 4-amino-5-bromobenzamide hydrochloride;

Melting point 219-221 ° C; N- (l-p-chlorobenzylpiperid-4-yl) -2-methoxy-

^ amino-S-chlorobenzamide hydrochloride;

Melting point 253-256 ⁰ C. Example 4

N- (l-Benzylpiperid-4-yI) -2-methoxy-4-amino-5-chlorobenzamide fumarate _{(C 2} OH _{24 ClN 3} O ₂ · C ₄ H ₄ O ₄ )

A hot solution of 3.75 g of N- (1-betu-ylpiperid-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 were added. The solution was filtered and the filtrate cooled, whereupon the fumarate of the base crystallized; Yield 2.7 g, melting point 209-210 ⁰ C. In a similar manner the following salts of the N- (1-Benzylpiperid-4-yl) -2-methoxy-4-amino-5-chIorbenzamids prepared:

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 Hj ₄ CIN ₃ O ₂ · C ₆ HgO ₇ H ₂ O) oxalate (C ₂₀ H ₂₄ ClN ₃ O ₂ · C ₂ H ₂ O ₄ ) a-ketoglutate (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 86-90 ⁰ C (Z); Melting point 234-235 ° C; Melting point 113-115 ° C; Melting point 170 ^° C. (d); Melting point 217-2i9 ° C.

Claims (1)

Claims: 1. N- (l-BenzyIpiperid-4-yI) -benzamides of the general formula I. H ₂ N N -CHj H ₂ N- <O> -COOH (II) OR ₁ whose amino group is optionally replaced by a in which: X is a chlorine or bromine atom, Ri is a straight-chain or branched alkyl group with up to 6 carbon atoms, R2 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- (1-Benzylpiperid-4-yl) -2-methoxy-4-atriino-5-chlorobenzamide and pharmaceutically acceptable ones Salts thereof. 3. A method for representing the compounds according to claim 1, characterized in that »· a) that one has a corresponding 2-alkoxy-4-amino-5-halobenzoic acid of the general formula II Acyl group is protected, or an active one Derivative of such an acid with a 1-benzyl-4-aminopiperidine of the general formula III H ₂ N (wherein R2 and R3 are as defined in claim 1 are) and, if the amino group of the benzoic acid reactant or its active Derivative is protected, this acyl protective group is then removed by hydrolysis; b) that a corresponding 2-alkoxy-4-aminobenzoic acid of the general formula IV COOH (IV) OR, or one of its active derivatives with a l-benzyl-4-aminopiperidine of the general Formula III converts and the reaction product of the general formula V H ₂ N- CONH N-CII ₂ OR ₁ R; Hill- (H ₂ (VII) (wherein Ri, R ₂ and Rj are as defined in claim I) 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 (wherein R ₂ and Ri are as defined in claim I and Hai is a halo gel) with (V) an N- (piperid-4-yl) -2-alkoxy-4-amino-5-halogenobenzamide of the general formula VIII H ₂ N CONII Ν —Η (VIII) (where X and Ri are defined as in Claim I. are) whose primary amino group is optionally protected by an acyl group, iimsct / t and, if the amino group of the benzine agent of the general formula VIII is protected is, this acyl protective group is then removed by hydrolysis. 4, procedure according to. To claim 3, feature a), characterized in that the reaction is carried out in an inert organic solvent at temperatures between -20 ° C and 15O ^0. 5, 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 i> the carrier.