DE3810552A1 - Esters and amides of indole-, benzo[b]thiophene or benzo[b]furancarboxylic acids or 4-amino-2-methoxybenzoic acids with N-heterocyclic or N-heterobicyclic alcohols or amines, processes for their preparation, pharmaceutical compositions containing them and applicator for administration thereof - Google Patents

Abstract

Compounds of the formula A-CO-B-D in which A, B and D possess the meaning indicated in Claim 1, processes for their preparation, and pharmaceutical compositions containing them having action against pain, in particular for the treatment of migraine, as antiarrhythmics and for the treatment of gastrointestinal disorders such as gastric secretion disorders, gastritis, peptic ulcer, dyskinesia of the bile tracts, spastic colon, irritable colon, Crohn's disease, ulcerative colitis, carcinoid syndrome and diarrhoea of varying origin (e.g. bacterial diarrhoeas, cholangenic diarrhoea, psychogenic diarrhoea) and for the improvement of gastric emptying, for the treatment of gastroduodenal and gastrooesophageal reflux, of oesophageal motility disorders, achalasia, hiatus hernias, cardiac insufficiency, hypotonia of the stomach, pylorus hyperplasia, paralytic ileus and Hirschsprung's disease, and also for the treatment of anxiety states, of psychiatric disorders such as social withdrawal phenomena, manic-depressive psychoses, psychoses and other illnesses connected with stress, disorders of the state of alertness such as geriatric syndromes, and also for the treatment of rhinitis, pulmonary embolism and for the improvement of the nasal absorption of other active compounds, e.g. of peptides, and the inhibition of emesis caused by cytostatics.

Description

The invention relates to compounds of the formula I, their preparation and they contain pharmaceutical compositions according to the claims 1 to 7.

Belgian patents 8 97 117, 9 00 425 and 9 01 274 disclose esters and amides of mono- and bicyclic, carbocyclic and heterocyclic Carboxylic acids and their antagonistic effect on the 5-HT₃-receptor described. Because of this property, the compounds can an action against the pain as well as antiarrhythmic and antipsychotic In particular, they are effective against migraine. It is further stated that the compounds are effective in the Elimination of serotonin - related gatrointestinal disorders and the acceleration of gastric emptying.

According to the invention it has now been found that within the Scope of the o. E. older patents, however novel compounds of the formula I according to claim 1, as well as their Acid addition salts or quaternary ammonium salts, one in the Belgian patents described compounds superior effect in the same indication area. Moreover, it was found that the compounds are suitable for the treatment of anxiety, of psychiatric disorders such as social withdrawal symptoms, manic-depressive psychoses, psychoses and others in connection Stress-related illnesses, disorders of alertness such as geriatric diseases, for the treatment of rhinitis, pulmonary embolism, to improve the nasal absorption of others Active ingredients, for. As of peptides such as Salmcalcitonin and for inhibition an emesis caused by cytostatics.  

The groups of formulas III and V can be in different configurations occur.

The orientation of groups III and V can be illustrated by means of an equatorial plane laid through the carbon atoms of the piperidyl ring with the nitrogen atom above and the alkylene bridge below the plane. Groups III and V have α configuration if substituent B is below the plane on the same side as the alkylene bridge. This corresponds to the endo orientation of tropine, etc. Substituent B is β- oriented if it is above the plane on the same side as the nitrogen atom. This is the exo orientation and configuration of the pseudotropin, etc. This endo / exo nomenclature is used below.

If in the groups III, V, VI and VII R₈ is alkyl, then this particular methyl.

Group IV is also known as Cinuclidinylgruppe. Usually this is a 3- or 4-quinuclidinyl and preferably a 3-quinuclidinyl.

The invention also relates to a process for the preparation of compounds of the formula I as well as their acid addition salts or quaternary ammonium compounds according to the following step:
Reaction of a corresponding compound of the formula VIII,

A-CO-OH (VIII)

wherein A has the above meaning, or a reactive derivative thereof, or a precursor of the acid or derivative with a suitable compound of the formula IX,

HB-D (IX)

wherein B and D have the above meaning, or a precursor of these Compound, and recovery of the obtained compounds of formula I as Bases or in the form of their acid addition salts or quaternary Ammonium salts.

The reaction according to the invention for the preparation of amides and esters can be done in a way that is necessary for the production of such compounds is common.

For example, the carboxyl group can be converted by conversion into a reactive Acid derivative, in particular for the production of amides, activated become. Suitable reactive acid derivatives such as the carboxylic acid imidazolides or N-hydroxy succinimides can be prepared by reaction of the corresponding Acids with N, N'-carbonyl-diimidazole or n-hydroxy-succinimide to be obtained. Furthermore, acid chlorides can also be used which are obtained, for example, by reaction of the corresponding acids with oxalyl chloride.

Suitable reaction temperatures are from about -10 ° to about + 10 ° C. In the case of compounds wherein B is NH and D is the Group IV, the reaction temperature can be up to 100 ° and the reaction is carried out in boiling methanol, ethanol or dioxane.  

Other suitable inert organic solvents are, for example Tetrahydrofuran or dimethoxyethane.

The pure endo- and exo-isomeric reaction products can be used per se known manner by means of chromatography or by crystallization be separated.

The compounds according to the invention can be converted into other compounds according to the invention, for example, converted in a known manner become.

Inasmuch as the preparation of the starting compounds is not specifically described are, these are known or can analogously known compounds be prepared, for example using known Process for the preparation of analogous compounds.

In the processes according to the invention, precursors of the starting compounds, if desired, also be used. Such precursors must be suitable, in a manner known per se in the starting material to be transformed. The implementation can also using the precursors and other starting compounds or whose precursors are made. The compounds obtained are in the compounds of the invention are converted in a manner known per se, for example, using the same reaction conditions, below which the precursors are converted into the starting compounds can.

The compounds according to the invention can be known per se Be isolated and cleaned.  

The free bases of the compounds of the invention may be incorporated into their salts be transferred. For example, acid addition salts may be used Known manner be prepared by reaction with a suitable Acid and vice versa. Suitable acids for salt formation are the hydrochloric acid, malonic acid, hydrobromic acid, Maleic acid, malic acid, fumaric acid, methanesulfonic acid, oxalic acid and Tartaric acid. Quaternary ammonium salts of the compounds according to the invention can be prepared in a manner known per se, for example by reaction with methyl iodide. It goes without saying that the acid addition salts and the quaternary ammonium salts of compounds of formula I are pharmacologically acceptable.

In the following examples, all temperatures are in degrees Celsius indicated and are uncorrected. All N.M. R.-Spektra are expressed in ppm (Tetramethylsilane = 0 ppm).

Example 1 5-Bromo-1H-indole-3-carboxylic acid-endo-8-methyl-u-azabicyclo [3.2.1] oct - 3-yl ester (Compound of formula I wherein A = II bond in the 3-position; R₁ = 5-Br; R₂ = H; X = NH; B = O; D = III in endo configuration; n = 2; R₈ = CH₃)

6.35 g (45 mM) of endo-8-methyl-8-azabicyclo [3.2.1] octan-3-ol (tropine) in 30 ml of absolute tetrahydrofuran are added at 0 ° C to 10 ° C with 17 ml a 2 molar solution of butyllithium in hexane. The mixture is stirred for 30 minutes, then the hexane is removed in vacuo and replaced by the appropriate amount of tetrahydrofuran, wherein the lithium salt is formed.

6.96 g (27 mM) of 5-bromo-indol-3-yl-carboxylic acid chloride in 20 ml of tetrahydrofuran are added to the above mixture and the resulting beige suspension stirred overnight at 20 ° C. The mixture is after in the usual way by distribution between methylene chloride and a worked up aqueous sodium carbonate solution, wherein said in the title Compound is obtained as a crude product. This is on silica gel (250 g), eluting methylene chloride, containing 10% methanol and 0.5% ammonia. The melting point of the racemic compound thus obtained is 261-262 ° (Methylene chloride / ethyl acetate).

In another embodiment, the 5-bromo-indol-3-yl-carboxylic acid chloride be reacted with N, N'-carbonyl-diimidazole, wherein the Imidazolide is obtained. This is added with the above lithium salt 10-15 ° C in tetrahydrofuran reacted.

Using the method described in Example 1 above and suitable starting compounds are obtained to the following compounds of the formula I:  

The compounds according to the invention show pharmacological activity and are therefore as pharmaceuticals for example for therapy usable.

In particular, the compounds according to the invention show an antagonistic Effect on the 5-HT₃ (serotonin) receptor, with the help of Standard tests can be found. For example, in one Test conducted by Riccioppo Neto in the European Journal of Pharmacology (1978) 49, 351-356, observed that the compounds invention of the influence of serotonin on the level of action potential of C-fibers on the isolated vagus nerve of the rabbit under conditions that allow between the action potentials, in the myelin-containing nerve fibers (A-fibers) and in The small non-myelin fibers (C-fibers) are formed as from B. Oakley and R. Schater in Experimental Neurobiology, A Laboratory Manual, University of Michigan Press, 1978, pages 85-96 is going to be different. Serotonin itself acts selectively the C-fibers and reduces the amplitude of the action potential in These fibers are dose-dependent. The effect of serotonin is known by 5-HT₃ antagonists such as metiterptine, methysergide, BOL-148, etc., which are believed to be D receptors for serotonin, however do not block M receptors, not inhibited (see Gaddam and Picarelli, Brit. J. Pharmacol. (1957), 12, 323-328). It therefore appears that serotonin underlies the level of action potential of C-fibers the influence of 5-HT₃-receptors - which are present on these fibers are - reduced.

This effect can be established by establishing a dose-response curve for serotonin (-10 ^-7 -5 x 10 ^-6 M). After the action potential of the nerve has stabilized, the serotonin is washed out and once the C-fiber action potential has reached the original amplitude, the compound to be tested is in a concentration of about 10 ^-18 M to about 10 ^-8 M incubated with the nerve for 30-60 minutes. Various concentrations of serotonin (usually 10 ^-7 moles to about 10 ^-4 moles) are then applied along with the subject compound of the invention, which is in concentrations present during the preincubation period.

The 5-HT₃ receptor antagonists according to the invention either block completely the effect of serotonin (non-competitive antagonist) or they cause a parallel shift in the serotonin response curve to the right (i.e., higher concentrations of Serotonin needed) (competitive antagonist). The pD'₂ or pA₂ value can be obtained in a manner known per se.

Another way of detecting 5-HT₃ receptor antagonism is a test in which the inhibition of the action of serotonin on the isolated rabbit heart was carried out according to the method of JR Fozard and AT Mobarok Ali, European Journal of Pharmacology (1978), 49, 109. 112, measured in concentrations of 10 ^-13 to 10 ^-6 M The pD'₂ and pA₂ values can be calculated therefrom in a manner known per se.

The effects of the compounds according to the invention as 5-HT₃- Antagonists in the treatment of pain is confirmed in the so-called "hot plate test" in doses of 0.1 to 100 mg / kg s. c. or p. O.

Another study to determine the 5-HT₃ antagonism of the compounds in humans in concentrations of 10 ^-8 M is feasible. In this case, a bladder is produced on the forearm of test persons by applying cantharidin. As soon as serotonin comes into contact with the subcutaneous tissue of the bladder, a pain is generated which can be estimated. The intensity of the pain is proportional to the amount of serotonin administered. This method is described in full detail by CAKeele and D. Armstrong in "Substances Producing Pain and Itch," Edward Arnold, London, 1964, pages 30-57. This pain-producing effect of serotonin can not be inhibited by serotonin D receptor antagonists such as lysergic acid diaethylamide or its bromo derivatives and it is therefore believed that this is triggered by 5-HT₃ receptors.

According to the described test, the area under the curve is measured, not the peak amplitude of the effects. The area under the curve is recorded by means of a linear integrator coupled to a pain indicator and confirmed by the subject. As the concentration of serotonin increases, a cumulative dose-response curve for serotonin is obtained. As soon as there is no effect after further administration of serotonin, the serotonin is washed out and the bladder is incubated with physiological buffer solution for at least 40 minutes prior to administration of the compound according to the invention, for example the preferred compounds of Examples 1 or 16. The test compound is preincubated with the bladder skin for 30 minutes at concentrations of 10 ^-8 M before different concentrations of serotonin are administered. The pA₂ values can be obtained therefrom in a manner known per se.

The compounds according to the invention can be used as 5-HT₃ antagonists, especially in the treatment of pain, especially migraine, cluster headache, a trigeminal  Neuralgia, as well as in the treatment of cardiovascular disorders, for example for the prevention of sudden death, as well as antipsychotics be used.

To achieve the aforementioned therapeutic effect are daily Indicated doses of 0.4 to 400 mg of the compound according to the invention, conveniently 2 to 4 times a day in doses of 0.1 to 200 mg or in prolonged-release form.

The compounds according to the invention also show an anti-arrhythmic Effect, as is their 5-HT₃-antagonistic effect in Standard tests can be taken. For example, the compounds inhibit an arrhythmia that is anesthetized with the help of norepinephrine Rats is caused. In this test, norepinephrine infusions given from 3 to 10 micrograms / kilo of carcass weight, until an arrhythmic phase is detected by ECG measurements which lasts longer than 10 sec. After checking from 3 Successive applications of norepinephrine will be the compound administered according to the invention in doses of 10 to about 500 Microgram / kilo of carcass weight, followed by additional norepinephrine administration. This shows that the arrhythmic phase is dependent is reduced or suppressed by the trial compound.

The compounds according to the invention are therefore indicated for the Use as antiarrhythmic drugs. The daily dose should be from about 0.8 to about 500 mg, which expediently divided into 2 to 4 times a day or in unit doses containing 0.2 to about 250 mg, or in sustained release form.  

However, the compounds according to the present invention are also suitable for the treatment of gastrointestinal disorders such as stomach secretory disorders, gastritis, peptic ulcer disease, dyskinesia of the biliary tract, spastic colon, irritable bowel, Crohn's disease, ulcerative colitis, Carcinoid syndrome and diarrhea of various causes (eg bacterial diarrhea, cholagogue diarrhea, psychogenic diarrhea) and further for improving gastric emptying, for treatment of gastroduodenal and gastroesophageal reflux, of esophagus motility disorders, achalasia, hiatal hernias, cardiac insufficiency, Hypotonia of the stomach, pyloric hyperplasia, paralytic ileus, and morbus Hirschsprung.

The effect of the compounds according to the invention in the treatment of gastrointestinal disorders, in the treatment of gastric secretion disorders, Gastritis, peptic ulcer disease, dyskinesis of biliary tract, spastic colon, irritable bowel, Crohn's disease, ulcerative colitis, carcinoid syndrome as well as diarrhea of different origin (eg bacterial conditioned diarrhea, cholongue diarrhea, psychogenic diarrhea) is evident in pharmacological studies in which the inhibitory Influence of 5-HT₃ antagonists on those caused by serotonin Gastrointestinal motility and secretion becomes apparent.

In a trial, the inhibition of serotonin at the isolated longitudinal muscle strips of the guinea pig induced contraction by 5-hydroxy-1H-indol-3-yl-carboxylic acid-endo-8-methyl-8- aza-bicyclo [3,2,1] oct-3-yl ester (compound of Example 16, hereinafter referred to as compound A), a characteristic Representatives of the compounds of the invention, measured.  

Extraction of the material Preparation of the longitudinal muscle strip of the guinea pig with adherent plexus myentericus

Male guinea pigs (200-400 g) are hit by a blow killed the head and bled. Part of the small intestine, about 2 cm is removed from the ileocaecal valve is removed. The mesentery is carefully removed and the ileum is placed over a glass rod. The longitudinal muscle layer is severed with a scalpel and with Help of a cotton swab removed by tangential rubbing.

Carrying out the experiment

Longitudinal muscle strips, 3-4 cm long, are placed in a bath containing a Tyrode solution at a temperature of 37 °, which is flushed with an oxygen stream containing 5% carbon dioxide, the Tyrode solution containing the following components (in m mol / l):
NaCl 137.0; CaCl₂ 1.8; KCl 2.7; MgCl₂ 1.05; NaHCO₃ 11.9; NaH₂PO₄ 0.4; Glucose 5,6.

The strips are exposed to a resting stretch of 500 mg. The contractions are registered with the help of an isotonic pendulum lever. After adjusting the balance (during 30 minutes) is Carbachol in a - triggering - concentration at intervals of 10 minutes until a corresponding constant Effect shows.  

Placement of concentration-response curves

Non-cumulative concentration-response curves for serotonin become created due to the addition of increasing concentrations of Serotonin to the organ bath at intervals of at least 15 minutes Reactions. For this purpose, the tissue is left with each concentration of serotonin come in contact for 1 minute. Each strip will used only to accommodate two concentration-response curves; the first for serotonin alone and the second for serotonin in the presence from an inhibitor-initiating concentration of the antagonist, d. i. Connection A. Each strip serves as its own Control. In doing so, the antagonists are allowed to enter serotonin 10 minutes on the fabric act. The for the contractions Values obtained from different preparations are expressed as percentages the maximum response to serotonin plotted, with a logarithmic Concentration-reaction curves is obtained. inhibition constants are expressed in terms of pA₂ values which are graphically below Using common methods (ARUNLAKSHANA and SCHILD 1959; MacKay 1978).

Addition of compound A at a concentration of 10 ^-6 mol / l completely inhibits the serotonin-induced contraction.

In another experiment, the inhibition of cholera toxin induced secretion measured by the compound A.  

Material and test preparation

NMRI mice of male sex weighing 20 to 30 g allowed to fast for 24 hours, but with water ad libitum is available. 1 hour before the administration of cholera toxin the animals each with 300 .mu.m / kg of the compound A by i. p. administration pretreated.

Carrying out the experiment

Each animal is given 200 μg cholera toxin using a gavage per os. administered. Thereafter, each with 2 ml of Tyrode's solution (see above) rinsed. 3 hours after her first administration the Compound A is administered again. 4 hours after the start of the experiment the animals are killed and their gut content is weighed.

The intestinal contents are usually increased under the influence of cholera toxin. This process is accomplished by administration of compound A in prevented a dose of 300 μg / kg to about 50%. An increase in the Dose of compound A has no further reduction in intestinal contents result.  

The compounds according to the invention, for example the compound A, which takes the form of the free bases or in the form of their acid addition salts or quaternary ammonium salts can inhibit above at doses of 0.03 to 1.0 mg / kg animal body weight i. v. administration and at doses of 0.1 to 3.0 mg / kg animal body weight when administered orally, those caused by serotonin gastrointestinal motility and secretion.

In a further experimental arrangement, the inhibition of 5-Hydroxytryptophan induced intestinal motility increase by the Compound A measured.

Material and test preparation

Male NMRI mice (weight 18-32 g) will be 20 hours before the start of the trial deprived of the food. The drinking water is not limited. Through a grid, the animals are separated from the litter and the feces. at Beginning of the experiment, the animals are spent in individual cages, in which case also the drinking water is withdrawn.

All animals are at the beginning of the experiment with the compound A or with Saline (control) pretreated. The application takes place intraperitoneally, the injection volume is 0.1 ml / 10 g. Thirty Minutes after pretreatment, 5-HTP or saline (control) administered intraperitoneally (injection volume 0.1 ml / 10 g). Immediately thereafter, an activated carbon slurry is administered orally (10% Suspension in water; 0.1 ml / 10 g). 45 minutes after the start of the experiment the animals are killed. Large intestine and small intestine from the stomach to the rectum are taken. For each animal, the transit route is determined d. H. the distance from the front of the activated carbon circle in the  Intestine was covered. This route is given in%, based on the total gastric rectum, and referred to as% transit. Each different treatment method is used on at least 3 animals repeated. The individual transit values are averaged.

The potency is indicated by ED50. It's the dose which is capable of increasing motility caused by 5-HTP to reduce by 50%. The ED50 is determined graphically.

The compounds according to the invention inhibit in the above experiment in Doses of 0.05-1.0 mg / kg animal body weight at i. v. administration and at doses of 0.1-3.0 mg / kg animal body weight when administered orally those caused by serotonin, formed from 5-hydroxytryptophan gastrointestinal motility increase.

As an advantage, it should also be noted that the non-stimulated, basal motility through the compounds down to very high doses (56 mg / kg) is not inhibited.

The compounds of the present invention exhibit acceleration gastric emptying a particularly favorable and specific Effect and are therefore also suitable for the treatment of gastroduodenal and gastroesophageal reflux, from esophageal motili dysfunctions, achalasia, hiatal hernias, cardiac insufficiency, hypotension of the stomach, pyloric hyperplasia, paralytic ileus, Hirschsprung's disease.

The effect is shown when comparing the o. E. Compound A with the known compound METOCLOPRAMID (the MERCK INDEX 1976, ref. 6018) (hereinafter referred to as Compound B) in the "in vitro" trial, the To influence contraction of the smooth muscle of the stomach and at "in vivo" attempt to improve gastric emptying.  

The "in vitro" experiment is performed as described below

Male Dunkin-Hartley guinea pigs weighing 340 to 450 g left over night without food are going through Cervical cut killed, the stomachs removed and placed in a Krebs-Henseleit solution (NaCl 118.0, KCl 4.75, KH₂PO₄ 1.2, MgSO₄ 1.2, CaCl₂ 2.5; NaHCO₃ 25.0 and glucose 10 mM). These become segments (approximately 20 mm long, 3-4 mm wide (cut out with a flat cut, for examining voltage changes in the curcular muscle layer are suitable. The tissue sections are then in 30 ml an organ bath containing an oxygen-containing (95% O₂, 5% CO₂) Krebs-Henseleit solution given at 37 ° C.

The tissue is applied a gram of tension, then allowed to Adjust the balance for 45 to 60 minutes before standing electrical stimulation is performed. An intramural stimulation is using platinum wire electrodes, which are about 5 mm away attached, the current being obtained from a Farnell stimulator is delivered. Voltage changes are made using a Grass voltage transformer detected and on a multi-channel Grass recorder shown.

experimental design

Frequency response curves are first in the absence of an active substance and subsequently in the presence of a potentially effective Aktivstoffes set up with a pretreatment time of 45 minutes. The second curve is related to the first, to the degree of potentiation or antagonism. The tissues are in 5-minute intervals stimulated for 30 seconds each. Fresh tissue  are used to determine the interactions with the antagonists. Suitable solvent control studies are during of the entire studies.

statistical evaluation

Reactions are measured as changes in grade stress, however to get an easier comparison between the respective experiments, The data is modified to reflect the changes as Show percentages.

"In vivo" studies Measurement of gastric emptying

14 hours before the measurement of gastric emptying is the animal deprived of the food. The experiment will be at low lighting and little Noises and disturbances and only by those experimenters performed daily with the guinea pig and contact who have also done the initial training to the guinea pigs to get used to the handling. Accordingly, in this experiment Subject the animals to the slightest stress.

The measurement of gastric emptying is determined by localization of Kodak plates (NS-2 T, 13 × 18 cm) made of polystyrene-covered barium sulfate Spheroids (approximately 30 mm diameter) using X-rays (50 KV, 30 m A, 0.5-0.8 s). The plates will be swallowed by the guinea pigs after this in the back part of the mouth in 0.2 ml of 1% carboxymethylcellulose with 0.05 ml of glycerol were introduced to make a quick and voluntary sip.  The passage of the spheroids is followed for 3 to 4 hours: during these periods the animals are kept in their cages and only 5 minutes before X-ray examination (at 30- to 60-minute intervals) taken out, and then in a holding cage made of Plexiglas be given, in which they are comfortable in one fixed position: the holding cage is well dimensioned (33 × 15 cm, and 13 cm high) to a guinea pig with a To keep weight between 450 and 550 g between foam-lined sides and an animal trained to go into the cage would Do this and stay calm and not be stressed during the treatment with x-rays.

experimental design

The gastric emptying is determined as the number of spheroids, who leave the stomach. 6 guinea pigs are given at each dose unit of the active substance used and the results with those of Guinea pigs who have received the appropriate carrier. The significance of the differences between active and control results is recorded using the Mann-Whitney U test. The mean error deviations (S.E.M.) are removed from the original ones Data calculated.

active ingredients

The o. E. Compound A is used as hydrochloride and Compound B as Monohydrochloride used. The salts are distilled for examination Water dissolved.  

results "In vitro" tests

A field stimulation of a circular muscle originating from the stomach of a Guinea pig gets, calls frequency-dependent contractions out. The contractions are made both by the compound A, as also reinforced by the compound B. Here, the connection A at least 100 times more effective than Compound B.

"In vivo" tests

The i. p. Administration of compounds A and B causes an improvement gastric emptying, using Compound A in this experiment at least 50 times more active than the connection B.

Assessment of the results

From the results of the above experiments it can be seen that the compound A of the present application in the investigations carried out has a superior effect. The compound A proves itself not only as highly effective in the conducted investigations, but It is also characterized by a practical lack of side effects out.

The compounds according to the invention, which are in the form of the free bases or in the form of their acid addition salts or quaternary ammonium salts in the above salts improve in doses of 0.03 to 1.0 mg / kg animal body weight at i. v. administration and in Doses of 0.1 to 10.0 mg / kg animal body weight when administered orally Gastric emptying in a guinea pig.  

For the application of the compounds according to the invention for the treatment of gastrointestinal disorders, etc. as well as to improve the Gastric emptying, etc. depends on the dose of the compounds according to the invention or their acid addition salts or quaternary ammonium salts from the particular compound used, the mode of administration and the desired treatment. In general, however, will be satisfactory Results when administered in daily doses from about 0.01 to about 10 mg / kg animal body weight, with the Administration in smaller doses 2 to 4 times a day or in delayed-release form to be held. For larger mammals, the daily administered Amount of about 0.5 to 599 mg, preferably from 20 to 100 mg, in particular from 20 to 40 mg. Dosage Forms for are suitable for oral administration, from 20 to 100 mg of the Compounds according to the invention or their acid addition salts or quaternary ammonium salts together with solid or liquid pharmaceutical Contain carriers or diluents and 2 to 4 times daily be administered.

The compounds according to the invention are generally well tolerated. The compounds also show no mutagenic in the AMES test Effect.

The suitability of the compounds summarized under the formula I and their acid addition salts and quaternary ammonium salts for treatment of psychiatric disorders can be the results of the subsequent Tests are taken:  

A study

A male mouse acting as an intruder in a cage with a domesticated, male, adult mouse is seated only slight signs of social activity and a strong defensive posture. Benzodiazepines and analogues increase the proximity activity the invading mouse in such a situation (DIXON, TRIANGLE 21, 95-105 95-105 [1982], KRSIAK, M., Br. Journal Pharmacol. 55, 141-150 [1975]). The compounds of formula I increase in doses of 0.1 to 1 mg / kg of approximate social activity.

study B

Using a slightly different methodology compared to Study A with a larger cage that gives the mouse greater freedom of movement allowed, it was found that the compound A 45 minutes after i. p. Administration at doses of 0.01 to 100 micron / kg the invading mouse increases social behavior.

study C

The situation described in Study A is changed, with a Encounter between male mice is induced during 6 hours without food remained. It turns out that the under the formula I summarized compounds and their acid addition salts and quaternary ammonium salts at doses of 0.01 to 1 mg / kg lengthen rapprochement (K. Hausamann, A.K. Dixon, Physiol. Behav. 1982, 28, 743-745).  

Results of Studies A, B and C

In the described studies improve those summarized under the formula I. Compounds and their acid addition salts and quaternary Ammonium salts, the social relations of experimental animals in such Situations among each other, where normally stress states such Would prevent behavior. Accordingly, the results show These experiments that the combined under the formula I compounds and their acid addition salts and quaternary ammonium salts are the stress caused by the social stress To compensate.

study D

A stretched expectation in the mouse shows an ambivalent Conflict situation caused by suspected anxiolytics (Käsermann H. P., Psychopharmacology [1986] 89: 31-37) is inhibited. The connections of the formula I and their acid addition salts and quaternary ammonium salts shorten, if administered 2 hours before, the Duration of the stretched expectation of mice, focusing on one elevated platform. It can be concluded that the compounds are able to create a nonspecific anxiety that is under Stress-related circumstances arise, reduce and thus anxiety-relieving to act.

study e

Mice that are brought into a new environment, for example by Moving from one room to another by means of a car, pointing an increase in plasma corticosterone levels, taking benzodiazepines and barbiturates can be reduced (Lahti R.A., Borsulm C.,  Res. Comm. Chem. Path. Pharm. 11: 595-603, G. Le Fur et al., J. Chem. Pharm. Exp. Ther. 211: 305-308). The compounds of the formula I and reduce their acid addition salts and quaternary ammonium salts Stress-related corticosterone levels in doses of 0.1 to 10 mg / kg p. o. Compound A reduces stress-related corticosterone levels at doses of 1 to 10 mg / kg p. o., while doses of 0.1 to 0.3 mg / kg increase the plasma levels of this hormone. The profile of the connections Formula I is diazepam-like in this experiment.

In summary, the results of these studies show that the compounds of the formula I and their acid addition salts and quaternary ammonium salts the social behavior in the encounter promote stressful situations. This suggests that these compounds are useful for the treatment of anxiety as well as of psychiatric disorders, wherein the treatment of social withdrawal symptoms, manic-depressive psychoses and other related appears with stressed diseases appears. The increase of Corticosterone also suggests that these compounds the Improve wakefulness and thus a potential use in the treatment of disorders of this alertness, as occurs, for example, in geriatric diseases, Offer.

The doses of the compounds to be administered daily for the indications depend on the type and severity of the disorders to be treated from. A suitable dosage range, as determined by the results of this Studies are suggested to be from about 0.01 to about 50 mg / kg / person / day administered in a single or multiple divided doses.  

The compounds of formula I and their salts may be for use to treat psychiatric disorders as usual Way, in particular enteral, preferably orally, for example in the form of tablets and capsules, or parenterally in the form of injection solutions or suspensions. Suitable pharmaceutical Carriers and diluents for oral administration Polyethylene glycol, polyvinylpyrrolidone, mannitol, lactose, etc., Granulating agents and decay accelerating agents such as starch and Alginic acid, binders such as stearic acid and gelatin, lubricants such as Magnesium stearate, stearic acid and talc. Suspensions can be preservatives such as ethyl p-hydroxybenzoate, suspending agents such as Methylcellulose, surfactants, etc. included. The parenteral forms are suitably buffered, aqueous solutions (pH between 4 and 5).

For the treatment of rhinitis, pulmonary embolism and improvement the nasal absorption of other agents, eg. Of peptides, it is Suitably, the compounds of formula I and their acid addition salts and administer quaternary ammonium salts via the nasal mucosa.

The nasal route provides a simple and quick to finish Method of administration, which is easily carried out by the patient himself can be, for. By administration of a liquid nasal administration form, for example, a nasal spray or dripping solution with the help of a Nasalapplikators, or by inserting one with the Active ingredient soaked gelatinous sponge, as well as further blowing the galenic form as a powder in the nostrils.  

In the liquid nasal administration form, the compounds of the formula I and their acid addition salts and their quaternary Ammonium salts in a proportion of 1 to 30%, preferably from 5 to 20%, in particular from 10 to 15% (w / v) be present.

In particular in the preparation of liquid nasal administration forms is the risk of contamination with pathogenic or other always pay attention to undesirable microorganisms. The procurement a suitable, fully compatible preservative to avoid contamination z. B. with pathogenic or other unwanted microorganisms, poses a problem in the production of nasal forms of administration. It is particularly critical for nasal pharmaceutical compositions in which the risk of Contamination is particularly high. The preservative should not only be able to check the initial contamination z. B. during the Formulation and filling the composition in the container too avoid, but also the other possible contamination during use, especially when administered multiple times a single container / applicator is required. Especially arise there problems where z. As a Nasalapplikator, which is often the case after Use for months before being used again. During this phase, the selected preservative can be inactivated be, for. B. by adsorption to the inner walls of the applicator, by heat removal, or if the preservative reasonably is volatile, by escaping from the applicator. Furthermore exists the danger that during the actual use phase (at multiple Administration with a single applicator can do this  Phase over several days or weeks), the applicator leak or otherwise undesirable microorganisms or otherwise Germs from the atmosphere or from the nostrils into the applicator penetration. Furthermore, the composition can last for shorter periods higher temperatures, eg. B. during transport or storage exposed his.

In addition to the o. E. Difficulty is a liquid nasal administration also be well tolerated, especially at the direct application site.

The liquid nasal administration form should, for. B. neither the nasal mucosa irritate (eg cause no significant irritation), still cause a significant reduction in the ciliary rate of movement.

According to the invention, it has now surprisingly been found that the nasal Administration of suitable liquid administration forms the compounds of the formula I and their acid addition salts and their contain quaternary ammonium salts, the high stability and Satisfy norms for nasal administration and for a use in nasal spray applicators are suitable, wherein The administration can take place in several doses (bumps), i. H. in Applicators, which are capable of a number of individual doses over z. B. to deliver a period of several days or weeks can, if you use benzalkonium chloride as a preservative. Surprisingly, it has also been found that the use of Benzalkonium chloride, even at the low levels needed for preservation Concentrations, the nasal absorption of the compounds of  Formula I and their acid addition salts and their quaternary ammonium salts favorably influence the initial bioavailability of the May increase compounds on nasal administration.

Accordingly, this part of the present invention relates to a first aspect containing a liquid, nasal dosage form

• 1) compounds of the formula I and their acid addition salts and quaternary ammonium salts,
• 2) a preservative, in particular benzalkonium chloride and
• 3) a liquid diluent or carrier suitable for Application on the nasal mucosa.

Preferably, the proportion of benzalkonium chloride in the inventive Compositions about 0.002 to about 0.02, especially about 0.01% (weight / volume) of the total composition.

According to the invention, the o. E. Administration forms e.g. B. as drops or administered as a spray on the nasal mucosa. As below however, they are preferably described as a spray, i. H. as finely divided droplets. One more way, the o. e. liquid nasal administration in contact with the nasal mucosa to bring is to make a gelatinous one Sponge (SPONGOSTAN) soaks and then sponge in the nostrils introduces.  

It is expedient to use as liquid diluents or carriers Water (pharmaceutical grade). Particularly preferred is a aqueous salt solution. The liquid nasal administration forms according to the invention are formulated to be administered allow over the nasal route. For this purpose, they can, for. Belly Min. amounts of other desired constituents or excipients, z. B. additional preservatives, or z. B. ciliary stimulants like caffeine, included.

The liquid nasal administration forms according to the invention have preferably a pH of 5.5 to 6.

The liquid nasal administration forms should also have suitable isotonicity and viscosity. Preferably, they have an osmotic pressure of about 260 to about 380 mOsm / liter. The desired viscosity of the compositions of the invention depends on the particular form of administration, e.g. B. whether nasal drops or a nasal spray are administered. For nasal drops, a viscosity of about 2 to about 40 × 10 ^-3 Pa · s is suitable. For nasal sprays, a viscosity of less than 2 × 10 ^-3 Pa · s is suitable.

The liquid nasal administration forms can of course also other ingredients, especially conventional pharmaceutical contain applicable surfactants. In this context and as a further aspect of the present invention it has been found that the use of surface-active compounds in the nasal Administration of the compounds their absorption through the nasal mucosa increased and the initial bioavailability improved. In this Case are non-ionic surfactants, for example  Polyoxyalkylenäther higher alcohols z. B. the general Formula XXXVI,

wherein RO is the residue of a higher alcohol, especially a higher alkanol such. As lauryl or cetyl alcohol, or an alkylphenol, or a sterol, especially lanosterol, dihydrocholesterol or cholesterol, and mixtures of two of the more such ether preferred. Preferred polyoxyalkylene ethers useful in the present invention are polyoxyethylene and polyoxypropylene ethers (ie where n ' in the above formula is 2 or 3), especially lauryl, cetyl and cholesteryl polyoxyethylene and polyoxypropylene ethers, as well as mixtures of two or more such ether.

Particularly suitable polyethers for use according to the invention are those in which the average of the repeating units in the polyoxyalkylene moiety (x in the above formula) is between 4 and 75, especially between 8 and 30 and most especially between 16 and 26. The polyethers can be obtained according to known methods. A large selection of such products is commercially available and is z. From Amerchol under the brand name Solulan®, from KAO Soap, ICI and Atlas under the brand names Emalex®, Brÿ® and Laureth® and from Croda under the brand name Cetomacrogol®.

Examples of polyoxyalkylene ethers suitable for use according to the invention, e.g. B. (POE = polyoxyethylene ether, POP = polyoxy propylene ether, x = average of the repeating units in the POE / POP part) are listed below:

• 1. cholersteryl ether:
  • 1.1 Solulan® C-24 - POE, x = 24
• 2. Ether of Lanolin Alcohols:
  • 2.1 Solulan® 16 - POE, x = 16
  • 2.2 Solulan 25 - POE, x = 25
  • 2.3 Solulan® 75 - POE, x = 75
  • 2.4 Solulan® PB-10 - PPE, x = 10
  • 2.5 Solulan® 98 - POE, x = 10 - partially acetylated
  • 2.6 Solulan® 97 - POE, x = 9 - fully acetylated
• 3. Lauryl ether:
  • 3.1 Emalex® 709 / Laureth® 9 - POE, x = 9
  • 3.2 Laureth® 4 / Brÿ® 30 - POE, x = 4
  • 3.3 Laureth® 23 / Brÿ® 35 - POE, x = 23
• 4. Cetyl ether:
  • 4.1 Cetomacrogol® - POE, x = 20 to 24

Lanolin alcohols are also known as wool fat alcohols and are a Mixture of cholesterol, dihydrocholesterol and lanosterol.

Preferred polyethers for use according to the invention are cholesteryl polyoxyethylene ethers, ie polyethers of the formula XXXVI, wherein n ' = 2 and RO is a cholesteryl radical, especially those polyethers in which the number of repeating units in the polyoxyethylene part is 16 to 26, especially about 24 ,

Preferably, such polyethers are free of impurities, in particular from other polyoxyalkylene ethers. Preferably, they contain at least 75%, more preferably at least 85%, and most preferably at least 90% (weight) of pure cholesteryl polyoxyethyl ether.

If a surfactant, e.g. As a polyoxyalkylene ether used is, the present in the compositions of the invention Amount of the particular surfactant used, from the administration form (eg drops or spray), as well as from the depending on the desired effect.

In general, the amount of surfactant used By means of between about 2.0 and about 200 (preferably up to about 100, especially up to about 20), especially between about 5 and about 30 (preferably to about 15) and especially about 10 mg / ml.

For nasal administration, the liquid nasal administration forms preferably in an applicator equipped with a device which is the application of the composition to the Nasal mucosa allows, for. In a nasal spray applicator, brought.

Such applicators are known per se and include those which for administration of liquid preparations as drops or spray on the nasal mucosa are suitable. Because the dosage of the compounds of formula I and their acid addition salts and their quaternary Ammonium salts should be as accurate as possible, is the use of spray applicators, in which an accurate regulation of the administered Amount is possible, in general preferred. Suitable admin  delivery devices are z. B. atomizers such as pump sprayer or spray cans. In the latter case, the applicator is an inventive Composition as well as a propellant for use in a nasal spray applicator. The atomizer is with a suitable spray device, which the Applying the composition to the nasal mucosa allows Provided. Such devices are generally known.

The container, for. A nasal spray applicator, an amount of the composition, which for a single nasal dosage or for the Administration of several dosages e.g. Over a period of several Days or weeks are sufficient. The quantities of single doses will be preferably the o. e. Correspond to cans.

Accordingly, the invention also relates to:

• A ^V. an applicator containing a liquid nasal administration form which contains the following components:
  • 1) compounds of the formula I and their acid addition salts and their quaternary ammonium salts
  • 2) a preservative, especially benzalkonium chloride, and
  • 3) a liquid diluent or carrier suitable for administration to the nasal mucosa,
• wherein the applicator is provided with a spraying device, which apply the pharmaceutical composition to the Nasal mucosa allows, as well  
• B ^v . a method for administering compounds of formula I and their acid addition salts and their quaternary ammonium salts to persons in need of such treatment, characterized in that a galenic form suitable for nasal administration and those mentioned above under A ^V. contains defined components 1, 2 and 3 and optionally also a surface-active agent administered to oe persons by the nasal route.

Applicators as defined above are preferably spray applicators for nasal use. Preferably, they allow administration the composition contained in individual doses of about 0.05 to about 0.15 ml, z. B. about 0.1 ml.

Suitable compositions as well as the individual components 1, 2 and 3 for use in an applicator are those previously described. The for the method B ^V. The appropriate dosages of the invention also correspond to the dosages given earlier.

Furthermore, the invention relates to a method for producing a containing liquid nasal administration form

• ) Compounds of formula I and their acid addition salts and their quaternary ammonium salts
• 2) a preservative, especially benzalkonium chloride, and
• 3) a liquid diluent or carrier suitable for administration are suitable for the nasal mucosa, and optionally a surfactant suitable for administration the nasal mucosa is suitable,

the process being characterized in that the components thoroughly mixed together and, if desired, the resulting Composition in an applicator equipped with a spray device which is the administration of the composition thus obtained on the nasal mucosa allows. Furthermore, with the obtained composition a sponge (SPONGOSTAN) soaked and the so impregnated sponge are introduced into the nostrils.

The stability of the composition according to the invention can be reduced to conventional Be determined manner.

The compositions according to the invention containing benzalkonium chloride, are stable against contamination by germs, eg. B. according to standard tests, as described by S. Urban et al. in Zbl. Bact. Hyg. I Dept. Orig. B. 1972, 478-484 (1981 and S. Urban, Acta Pharm. Technol. 22, 247-253 (1976). For example, the cell number of the standard bacteria, namely E. coli ATCC 8739, Pseud. aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and standard fungi Cand. albicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergillus ATCC 16404 and Pen. steckii ATCC 10499, after inoculation of the composition reduced to 0.1% or less within 24 hours, as shown by standard tests.

In a stability test, the nasal spray composition of the Example 43 below for 3 months at 30 ° C under a nitrogen atmosphere stored in a glass container. Pseudo aeruginosa ATCC 9027, Staph. aureus ATCC 6538, Strept. pyogenes ATCC 8668 and the Fungi Cand. Albicans ATCC 10231, Sacch. cerevisae ATCC 9763, Aspergilli ATCC 16404 and Pen. stechii ATCC 10499 were added until to a cell number of about 2 x 10⁵ organisms in the inoculated fluid.  Within 2 hours, the germ count had decreased to less than 0.1%. Within 4 weeks, no germs could be detected become.

In addition, the compositions are well tolerated, as from standard tests shows, for. For example, less than 50% inhibition of ciliary Movement frequency observed 20 minutes after administration, according to the Microphotographic oscillographic method of L. Chevance et al., Acta Otolaryng. 70, 26-28 (1970).

The liquid nasal administration form according to the invention has advantageous properties, in particular allows for administration a rapid absorption of the active substance in the body. So already can after about 5 to 10 minutes after nasal administration 200 ng of the o. e. Compound A can be detected in plasma. For oral administration is this drug concentration in the plasma after about 30 reached up to 40 minutes. The general bioavailability of the compounds of the formula I and their acid addition salts and their quaternary Ammonium salts over a period of 6 hours is after nasal administration in the same order of magnitude as after oral administration.

The same favorable results are obtained if the compounds of the formula I and their acid addition salts and their quaternary Ammonium salts administered in a galenic form, which are in the form of a powder and introduced by blowing into the nostrils becomes.

When administered by the nasal route, a beneficial effect of the compounds achieved according to the invention against rhinitis. This expresses in a reduction of nasal fluid secretion. there  it is advantageous that the application of the substances Ciliary movement of the nasal mucosa is not affected.

Necessary doses: 0.01 mg to 1 mg / shock once or several times a day applied.

The determination of the effect of compound A on pulmonary embolism can as described below:

Reflexology is performed on spontaneously breathing rabbits, with a continuous infusion of sodium pentobarbital were anesthetized. Both vagi remain intact, the systemic arterial blood pressure, the heartbeat, the volume of respiratory air, the Respiratory speed and platelet count are recorded.

Control of the embolization reflex

By injection of 1 mg Sephadex G 25 beads suspended in 0.2 ml Dextran (6%) at 1 minute intervals in 6 control rabbits Embolization reflexes caused. The at pretreatment with the compound A achieved improvement in a) mortality and b) cardiovascular and respiratory reflex responses to the miliary pulmonary embolism are analyzed. The result is a clear preventive Effect of compound A on pulmonary embolism.

The compounds of the formula and their acid addition salts and Quaternary compounds surprisingly increase absorption of other drugs, in particular of peptidic structure, e.g. B. Salmon calcitonin, if administered together nasally.  

For example, with combined use of Compound A increases (15 mg) and salmon calcitonin (100 IU), of which half each introduced into each nostril, the bioavailability of salmon calcitonin (AVC up to 2 hours) in rhesus monkeys of 0.08 IU / ml / h in Plasma from 1.632 IU / ml / h.

To achieve a beneficial effect in the above indications should the compounds of the formula I and their acid addition salts quaternary compounds to the body at a dose of 0.01 mg / kg to about 10 mg / kg animal body weight are supplied. In humans should the daily orally administered dose of 5 mg to about 300 mg Compounds of the formula I are suitable, for example in divided doses up to 4 times a day as in the case of the compound A in the order of about 40 mg / p. o. be administered.

For nasal administration, the dose should be from 0.13 to 0.4 mg per kg Body weight, d. i. about 100 mg to 300 mg or 10 to 30 bursts of Nasal sprays per patient amount.

When co-administered with another drug depends the administered amount of a compound according to the invention from the other Active ingredient and the type of treatment. Usually one uses half to ¹ / ₁₀ of the dose of the other drug.

The compounds of the formula I and their acid addition salts and Quaternary compounds also inhibit this through cancer treatment Cytostatic-induced vomiting in animals as standard tests for example, inhibition of cisplatin (10 mg / kg  i. v.) vomiting in ferrets in doses of approx. 0.005 to about 0.5 mg / kg i. v. (according to the method described in the Europ. Patent Application 2 01 165).

Accordingly, the compounds of formula and their acid addition salts and quaternary compounds for the treatment of a Cytostatic agent induced emesis can be used.

The compounds may be incorporated into the following pharmaceutical compositions to be brought.

example 39 Tablets for oral administration

Tablets containing the ingredients listed below are prepared in a manner known per se and in the described Indications used.

Compound A in the form of the hydrochloride (corresponds to 15 mg free base) | 16.8 mg Hydroxy-propyl-cellulose 1.2 mg corn starch 12.0 mg lactose 93.0 mg silica gel 0.6 mg Magnesium stearate  1.4 mg Tablet weight | 125.0 mg

example 40 Capsules for oral administration

Capsules containing the following ingredients are on manufactured known manner and in the described indications used.

Compound A in the form of the hydrochloride (equivalent to 15 mg base) | 16.8 mg lactose 29.0 mg silica gel 1.2 mg Magnesium stearate  3.0 mg Capsule weight | 50.0 mg

example 41 Injection solutions for i. v. administration

An indication solution is prepared in a known per se and in a dose of 10 mg of the active ingredient per day in the described Indications used.

example 45 Capsules for oral administration

5 mg and 15 mg capsules (hereinafter A and B) containing the below cited constituents, are known per se prepared and in the above indication 2 to 4 times a day in the case composition A and once a day in case of composition B used.

example 43 Nasal composition for the treatment of rhinitis, pulmonary embolism or to improve the nasal absorption of other drugs

ingredients Amount of ingredients 5-Hydroxyindol-3-yl-carboxylic acid-endo-8-methyl-8-aza-bicyclo [3,2,1] o-t-3-yl-ester.HCl | 100 mg benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution) 0.6 ml Distilled water 0.4 ml

The resulting solution is filtered (eg through a 0.2 μm filter) and filled in a nasal spray can or a gelatinous sponge (SPONGOSTAN) soaked with it.

example 44 Nasal composition for the treatment of rhinitis, pulmonary embolism or to improve the nasal absorption of other drugs

ingredients Amount of ingredients 5-Bromo-1H-indole-3-carboxylic acid-endo-8-methyl-8-azabicyclo [3,2,1] oct-3-yl-ester | 50 mg benzalkonium chloride 0.1 mg NaCl (0.9% aqueous solution) 0.83 ml Distilled water 0.17 ml

The resulting solution is filtered (eg, through a 0.2 μm filter) and filled in a nasal spray can or a gelatinous sponge (SPONGOSTAN) soaked with it.

In the compositions according to Examples 39-44, for the Indications all listed in Examples 1-38 Active ingredients are used.

According to the present invention, compounds of the formula I prepared in pharmaceutically acceptable form, for example in the form of the free bases or in the form of pharmaceutically acceptable Acid addition salts or quaternary ammonium salts for use as pharmaceuticals, especially because of their use as 5-HT₃ antagonists, used to treat such diseases can, where the blocking of 5-HT₃-receptors have a favorable effect expect, for example, as a remedy for the pain, in particular Anti-migraine remedies, as antiarrhythmic agents, as a remedy for Serotonin-induced gastrointestinal motility and secretion and as a means of accelerating gastric emptying, but also for the treatment of anxiety, psychiatric disorders such as social withdrawal symptoms, manic-depressive psychoses, psychoses and other stress-related diseases, Disorders of wakefulness such as geriatric diseases, to Treatment of rhinitis, pulmonary embolism, to improve the nasal Absorption of other drugs and inhibition of cancer treatment with cytostatics z. B. Cisplatin-induced vomiting.

The preferred use is in the field of control agents of pain, especially migraine, as antiarrhythmic drugs, for the treatment of gastrointestinal disorders such as gastric leukemia  disturbances, gastritis, peptic ulcer disease, dyskinesia of the biliary tract, spastic colon, irritable bowel, Crohn's disease, ulcerative colitis, carcinoid syndrome as well as diarrhea of different origin (eg bacterial conditioned diarrhea, cholangene diarrhea, psychogenic diarrhea), as well as to improve gastric emptying, to treat gastroduodenal and gastroesophageal reflux, of esophageal motility disorders, Achalasia, hiatal hernias, cardiac insufficiency, hypotension of the Stomach, pyloric hyperplasia, paralytic ileus, Hirschsprung's disease, anxiety, psychiatric disorders, and the like Rhinitis, pulmonary embolism and improve nasal absorption other agents z. B. of peptides, wherein for the treatment of Rhinitis, pulmonary embolism and improve nasal absorption other agents nasal the compounds in one for nasal administration suitable galenic form takes place.

Very particularly preferred is the use for the inhibition of a Cytostatic drugs, in particular cisplatin-induced emesis.

The compounds according to the invention may be in the form of the free bases or in the form of pharmaceutically acceptable salts, for example suitable ones Acid addition salts and quaternary ammonium salts become. Such salts are of the same order of magnitude Effect like the free bases. The present invention accordingly relates also a pharmaceutical composition containing a compound of the formula I, an acid addition salt thereof or a quaternary one Ammonium salt thereof, together with a pharmaceutical carrier or diluent. Such compositions can be applied to Known manner can be prepared and can be used for example in Form of solutions or tablets or the described nasal forms be administered.

Claims (7)

1. Compounds of the formula A-CO-BD (I) where A is a group of the formula or the formula in which X, R₁, R₂, R₃, R₄ and B have the meanings given below and D may be selected from the following groups and their acid addition salts or quaternary ammonium salts. 2. A process for the preparation of compounds of the formula I according to Claim 1 and their acid addition salts or quaternary ammonium salts marked by Reaction of a corresponding compound of the formula VIII, A-CO-OH (VIII) in which A has the above meaning, or a reactive derivative thereof, or a precursor of the acid or derivative with a suitable A compound of the formula IX, HB-D (IX) in which B and D have the above meaning, or a precursor thereof Compound, and recovery of the obtained compounds of formula I as Bases or in the form of their acid addition salts or quaternary Ammonium salts. 3. Therapeutic composition containing compounds according to Claim 1. 4. Therapeutic composition according to claim 3 for use against pain, in particular for the treatment of migraine, as an antiarrhythmic and for the treatment of gastrointestinal disorders such as Gastritis, gastritis, peptic ulcer, dyskinesia  Biliary tract, spastic colon, irritable bowel, Crohn's disease, colitis colitis, carcinoid syndrome and diarrhea of various causes (eg bacterial diarrhea, cholongue diarrhea, psychogenic Diarrhea) and to improve gastric emptying, to treat Gastroduodenal and Gastroesophageal Refluxes, Esophageal Motility Disorders Achalasia, hiatal hernias, cardiac insufficiency, hypotension of the stomach, pyloric hyperplasia, paralytic ileus, Hirschsprung's disease, furthermore for the treatment of anxiety, of psychiatric Disorders such as social withdrawal symptoms, manic-depressive psychoses, Psychosis and other stress related Illnesses, disturbances of alertness such as geriatric illnesses, also for the treatment of rhinitis, pulmonary embolism and for the treatment of nasal absorption of other agents, e.g. B. of peptides as well as the inhibition of cytotoxic agents Emesis. 5. A nasal administration form characterized in that Compounds of formula I and their acid addition salts and quaternary Ammonium salts, a preservative and a liquid diluent or one suitable for use on the nasal mucosa Carrier contains. 6. A nasal administration form according to claim 5 for use against rhinitis and pulmonary embolism and to improve the nasal Absorption of other active substances, for example peptides. 7. An applicator for administering a dosage form according to Claim 5.