HK1053648B - Novel 1-(1-(hetero)aryl-1-perhydroxyalkylmethyl)-piperazine compounds, process for their preparation and medicaments containing these compounds - Google Patents

Description

1- [1- (hetero) aryl-1-perhydroxyalkylmethyl ] -piperazine compounds, process for their preparation and medicaments containing them

The invention relates to novel 1- [1- (hetero) aryl-1-perhydroxyalkylmethyl ] -piperazine compounds having tachykinin receptor antagonistic action and to medicaments containing these compounds. The invention also relates to a method for producing said novel piperazine compounds and to intermediate products of the production thereof.

Among the tachykinins are the naturally occurring neuropeptide substances P, neurokinin a and neurokinin B. Tachykinins act as potentiators of some of the receptors found in larger mammals and humans, such as neurokinin (═ NK) -1-receptor, NK-2-receptor and NK-3-receptor. Synthetic tachykinin receptor antagonistic compounds are generally classified by their relative ability to bind to one or more of the three receptor subtypes mentioned above. Tachykinins play an important role in physiological processes, for example in pain metastasis, emesis, in neurogenic inflammation, bladder inflammation, arthritic diseases or in asthmatic diseases.

Piperazine derivatives which act as NK-2 receptor antagonists are known from EP 0474561A 1.

Further piperazine derivatives which act as tachykinin receptor antagonists are known from WO 96/10568.

The object of the present invention is to provide active substances having tachykinin receptor antagonistic properties and improved action properties which are suitable, in particular, for the treatment of peripheral disorders, such as gastrointestinal functional and inflammatory disorders.

It has now surprisingly been found that a novel class of 1- [1- (hetero) aryl-1-perhydroxyalkylmethyl ] -piperazine compounds is distinguished by their tachykinin receptor antagonistic, in particular NK-2-receptor antagonistic, properties and the compounds have outstanding active ingredients against the peripheral system. The compounds of the invention are therefore particularly suitable for the treatment of peripheral disorders in which tachykinins, in particular neurokinin a, are involved as mediators, for example for the treatment and/or prevention of gastrointestinal functional and inflammatory diseases. Within the scope of the present invention, the concept of (hetero) aryl may include both aryl and heteroaryl residues.

The invention relates to novel 1- [1- (hetero) aryl-1-perhydroxyalkylmethyl ] -piperazine compounds of general formula (I)

Wherein

A represents naphthyl, phenyl optionally substituted by hydroxy, mono-or bicyclic heteroaryl or C optionally substituted by phenyl_3-6-an alkenyl group,

z is a group of the formula

A group of (1), wherein

R¹Can be hydrogen or lower alkanoyl, or with a compound selected from R²、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally lower alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R²represents hydrogen or lower alkanoyl, or with R¹、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally lower alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R³represents hydrogen or lower alkanoyl, or with R¹、R²、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally lower alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁴represents hydrogen or lower alkanoyl, or with R¹、R²、R³And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally lower alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁵represents hydrogen or lower alkanoyl, or with R¹、R²、R³And R⁴Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally lower alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

k represents a number of 0 or 1,

l represents a number of 0 or 1,

m represents a number of 0 or 1,

n represents a number of 0 or 1,

R⁶represents halogen or hydrogen and

R⁷represents a halogen or a hydrogen atom, or a salt thereof,

and physiologically tolerated acid addition salts of the compounds of the general formula I. Furthermore, medicaments containing compounds of the general formula I are also subject matter of the present invention. The invention also relates to a method for producing compounds of the general formula I and to intermediate products of said production.

If a substituent represents or contains an alkyl group in a compound of the formula I or in other compounds within the scope of the invention, the alkyl group may be straight-chain or branched and contain 1 to 4 carbon atoms. If the substituents in the compounds of the formula I are halogen, fluorine, chlorine or bromine come into consideration, chlorine being preferred. If the substituent contains a lower alkanoyl group, the lower alkanoyl group may be straight-chain or branched and contains 2 to 4 carbon atoms. The lower alkanoyl group is preferably acetyl.

The radical A is preferably a monocyclic heteroaryl radical, with thiophenes, furans and pyrroles being particularly suitable as monocyclic heteroaryl radicals, preference being given to thiophenes and furans. If A is a bicyclic heteroaryl, benzothiophene, benzofuran and indole are especially contemplated. If A is C optionally substituted by phenyl_3-6Alkenyl, the alkenyl may be linear or branched, especially 1-alkenyl.

If included in the group Z is selected from R¹、R²、R³、R⁴And R⁵One substituent of the group together with another substituent selected from the group being an optionally substituted lower alkyl or C_4-55-or 6-membered rings bridged by methylene substituted by alkylene, in particular 5-or 6-membered rings bridged by methylene, 1-dimethyl-methylene, 1-spiro-tetramethylene-methylene or 1, 1-spiro-pentamethylene-methylene are contemplated. Phase (C)The corresponding carbonyl-bridged 5-or 6-membered ring is a cyclic carbonate. The corresponding thiocarbonyl-bridged 5-or 6-membered ring is a cyclic thiocarbonate. K is preferably 1. N is preferably 0. Z is preferably an optionally substituted 1, 2-diphenol residue, a1, 2, 3-triphenol residue or a1, 2, 3, 4-tetraphenol residue. Carrying a substituent R¹、R²、R³And R⁴Are asymmetric and may occur in two different configurations. Z may thus occur in a number of stereoisomeric forms. The present invention includes, in addition to compounds of the general formula I which contain a mixture of stereoisomers of the group Z, also compounds of the general formula I which contain an isomerically pure group Z. Preferred radicals Z are wood-1, 2, 3, 4-tetrahydroxybutyl, leso-1, 2, 3, 4-tetrahydroxybutyl, arabic-1, 2, 3, 4-tetrahydroxybutyl, threo-1, 2, 3-trihydroxypropyl, erythro-1, 2, 3-trihydroxypropyl and glycerol-1, 2-dihydroxyethyl. Carbohydrates selected from the D-series of carbohydrates on which the group Z is based, mostly have the most beneficial results. Diastereomerically pure radicals Z are preferred.

Particularly preferred compounds of the formula I are selected from the following group of compounds:

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl ] -1-piperazinyl } butyl) -N-methylbenzamide;

(2S) -2- (acetyloxy) -3- {4- [ (3S) -4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] -1-piperazinyl } -3- (2-furyl) propyl-acetate;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- (4- { 2-furyl [ (4S) -2-oxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (1S, 2R) -2, 3-dihydroxy-1- (3-thienyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S) -2, 3-dihydroxy-1- (3-furyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (2-furyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R) -2, 3-dihydroxy-1- (3-thienyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R, 3S, 4S) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxyacetyl-1- (3-thienyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R) -2, 3, 4-trihydroxy-1- (3-thienyl) butyl ] -1-piperazinyl } -butyl) -N-methylbenzamide and

n- ((2S) -2- (3, 4-dichlorophenyl) -4- { 2-furyl [ (4S) -2-thioxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) -butyl) -N-methylbenzamide.

The compounds of formula I and their acid addition salts can be prepared as follows: the compound of the general formula II is reacted with a compound of the general formula II,

wherein R is⁶And R⁷As defined above, with the compounds of the general formula III,

A-B(OH)₂ III

wherein A is as defined above, and with a compound of the general formula IV,

wherein R is¹、R²、R³、R⁴、R⁵K, l, m and n are as defined above, and then, if desired, reacting the obtained compound of the formula I, wherein at least one is selected from R¹、R²、R³、R⁴And R⁵The substituent(s) represents hydrogen, by reaction with a compound of formula VIII,

R₈-COOH (VIII)

wherein R is⁸Denotes a straight-chain or branched alkyl radical having 1 to 3 carbon atoms, acylated in the radical Z or followed, if desired, by the compound of the formula I obtained, at least two of which are selected from R¹、R²、R³、R⁴And R⁵By carbonylation or thiocarbonylation with a reactive carbonyl-or thiocarbonylic equivalent (Synthesis) in the Z radical, or by reacting a compound of formula I, at least two of which are selected from R¹、R²、R³、R⁴And R⁵The substituent(s) represents hydrogen by reaction with a di-lower alkyl ketone or a C_5-6-conversion of a cycloalkylketone in the group Z into an optionally lower alkyl or C_4-5-5-or 6-membered ring-derivatives bridged by an alkylene-substituted methylene group, and, if desired, converting the obtained compounds of the general formula I into their acid addition salts or converting the acid addition salts into the free compounds of the general formula I.

May be as knownA method in which the reaction is carried out under the conditions of Boron Mannich (Boron-Mannich) reaction (see, for example, N.A. Petasis et al, proceedings of the American society of chemistry 120(1998)11798-11799, WO98/00398 or WO 00/24510). The compound of the formula II can thus be reacted in a one-pot process with a boronic acid of the formula III and a carbohydrate of the formula IV, optionally protected with a suitable protecting group, in a solvent which is inert under the reaction conditions. Suitable carbohydrate protecting groups are known, for example, from j.a.w.mcomie, "protecting groups in organic chemistry", Plenum press, 1973, or from t.w.green, p.g.wuts, "protecting groups in organic synthesis", Wiley and Sons, 1999. Suitable solvents are dipolar protic organic solvents such as lower alkanols, e.g. straight-chain or branched C_1-4-alkanols, preferably ethanol, or mixtures of suitable such solvents with water or with dipolar aprotic solvents such as lower haloalkanes, preferably dichloromethane. Suitable reaction temperatures are in the range between room temperature and the boiling point of the solvent or solvent mixture. The compounds of the formulae II, III and IV are preferably joined one after the other in the order given. It is likewise possible to join the compounds of the formula II first with the compounds of the formula IV and then with the compounds of the formula II. The chiral centers in the compounds of the formula I which are newly formed in these coupling reactions and carry the groups A and Z are usually formed to a large extent in diastereocontrol as "trans" products.

The compounds of the formula I which carry at least one free hydroxyl group in the radical Z can, if desired, be reacted subsequently with compounds of the formula VIII, whereby the free hydroxyl group of the radical Z is acylated. In this case, the free hydroxyl groups of the group Z are generally fully acylated. As acylating agents it is possible to use acids of the formula VIII or reactive derivatives thereof. Acid anhydrides and acid halides come into consideration in particular as reactive derivatives. The acylation reaction can be carried out in an organic solvent which is inert under the reaction conditions, preferably at a temperature in the range between-20 ℃ and room temperature. Suitable solvents are, in particular, aromatic hydrocarbons such as benzene or toluene, cyclic or open-chain di-lower alkyl ethers such as diethyl ether, tetrahydrofuran (═ THF) or dioxane, partially halogenated lower hydrocarbons such as dichloromethane or mixtures of these solvents. If anhydrides of acids of the formula VIII and acid halides are used as acylating agents, the acylation is preferably carried out in the presence of an acid-binding reagent. Suitable acid-binding agents are non-nucleophilic organic bases which are soluble in the reaction mixture, such as pyridine, triethylamine or 4-dimethylaminopyridine. The organic base used in excess can also be used simultaneously as solvent.

The compounds of the formula I in which the radical Z carries at least two free hydroxyl groups can, if desired, be reacted after their preparation as described above, instead of with compounds of the formula VIII, with a reactive carbonyl-or thiocarbonylic synthesis equivalent, by means of which the radical Z can be carbonylated or thiocarbonylated. The reaction can be carried out in a known manner. This makes it possible to react the compounds of the formula I in organic solvents which are inert under the reaction conditions. Suitable as reactive carbonyl-synthesis equivalents are, for example, phosgene or phosgene-like reactive substances such as bis- (trichloromethyl) carbonate (═ triphosgene), chloroformic acid-trichloromethyl ester (═ triphosgene) or, in particular, carbonyldiimidazole. N, N' -thiocarbonyldiimidazole is preferred as a suitable reactive thiocarbonyl-synthesis equivalent. An acid binding agent may be suitably added to the reaction mixture. Suitable acid binding agents are the acid binding agents given above for the reaction of a compound of formula I with a compound of formula VIII. Suitable reaction temperatures are in the range between about-20 ℃ and room temperature.

The compounds of the formula I in which the radical Z carries at least two free hydroxyl groups can, if desired, be reacted with a di-lower alkyl ketone or a C, after their preparation as described above, instead of with compounds of the formula VIII or instead of with reactive carbonyl-or thiocarbonyl synthetic equivalents_5-6-conversion of a cycloalkylketone in the group Z into an optionally lower alkyl or C_4-5-5-or 6-membered ring derivatives bridged by alkylene substituted methylene. Acetone is preferred as the di-lower alkyl ketone. As C_5-6Cycloalkyl ketones are preferably cyclopentanone and cyclohexanone.

If compounds of the formula I are to be prepared which contain a substituent R in the group Z¹、R²、R³、R⁴And/or R⁵Instead of hydrogen, it is preferred to start with a carbohydrate of the formula IV which contains a free hydroxyl group at least in the alpha-position of the aldehyde function. Advantageously from R thereof¹、R²、R³、R⁴And R⁵Starting from a compound of the general formula IV which represents hydrogen. The free hydroxyl groups can, if desired, be subsequently acylated, carbonylated, thiocarbonylated or reacted with suitable ketones in the manner described above.

The compounds of the general formula II are novel compounds which are suitable in an advantageous manner as intermediates for the preparation of novel active substances, for example for the preparation of tachykinin receptor antagonistic compounds of the general formula I.

The compounds of formula II can be prepared by reacting a compound of formula V,

wherein R is⁶And R⁷As defined above, X is halogen, especially iodine, with a protected piperazine derivative of the formula VI,

where SG is a cleavable protecting group, especially t-butyloxycarbonyl, and the reaction is followed by cleavage of the protecting group in a known manner. The reaction can be carried out in organic solvents which are inert under the reaction conditions, such as aromatic hydrocarbons, in particular toluene, or in cyclic or open-chain di-lower alkyl ethers, in particular tetrahydrofuran, or preferably in mixtures of these solvents, and in the presence of a base. Suitable as bases are non-nucleophilic organic nitrogen bases such as tertiary lower alkylamines, e.g. triethylamine. Suitable reaction temperatures are in the range between 50 ℃ and 100 ℃, preferably between about 70 ℃ and 90 ℃.

The compounds of formula V may be prepared by reacting a compound of formula VII,

wherein R is⁶And R⁷As defined above, in a known manner with an alkali metal halide of the general formula MX, where M is an alkali metal, in particular sodium, and X is as defined above, in particular iodine. The compounds of the general formula VII and their stereoisomeric forms are known, for example from EP 0474561 a1, and can be prepared according to the methods given in this specification or analogously thereto.

The compounds of the formulae III, IV and VI are known or can be prepared in a known manner by the person skilled in the art from known compounds. Preferred compounds of formula IV include D-xylose, D-lyxose, D-arabinose, D-threose, D-tetrose, and D-and L-glyceraldehyde.

The compounds of the formula I can be isolated and purified from the reaction mixture in a known manner. Acid addition salts can be converted in the usual manner into the free base and, if desired, the free base into physiologically tolerated acid addition salts in a known manner. As physiologically tolerated salts of the compounds of the formula I, the customary salts thereof with inorganic acids, for example sulfuric acid, phosphoric acid or hydrohalic acids, preferably hydrochloric acid, or with organic acids, for example lower aliphatic mono-, di-or tricarboxylic acids, such as maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, or with sulfonic acids, for example lower alkanesulfonic acids, such as methanesulfonic acid or trifluoromethanesulfonic acid, or benzenesulfonic acids, such as p-toluenesulfonic acid, optionally substituted on the benzene ring by halogen or lower alkyl, are considered.

The compounds of the general formula I contain a non-symmetric carbon atom in the gamma-position of the ring nitrogen atom in the 4-position of the piperazine ring, i.e. carrying the ring R⁶And R⁷Carbon atoms of substituted benzene rings^*C. Due to the asymmetric carbon atom, and to the asymmetric carbon atom carrying the groups A and Z, and possibly also due to the asymmetric carbon atom contained in the group Z, the compounds of formula IThe compounds may exist in the form of various stereoisomers. The invention includes both mixtures of optical isomers and isomerically pure compounds of the general formula I. Preferred compounds of the formula I carry a group R⁶And R⁷Carbon atoms of substituted benzene rings^*C has the S-configuration. If mixtures of optical isomers of the starting compounds, for example of the compounds of the formula II or of the compounds of the formula IV, are used in the synthesis of the compounds of the formula I, the compounds of the formula I obtained are also in the form of mixtures of optical isomers. If the starting compounds are used in stereochemically pure form, stereochemically pure compounds of the formula I can also be obtained. Stereochemically pure compounds of the general formula I may be obtained from mixtures of optical isomers according to known methods, for example by chromatographic separation with chiral separating materials or by reaction with suitable optically active acids, for example tartaric acid or camphor-10-sulfonic acid, and subsequent resolution into the optically active enantiomers by fractional crystallization of the diastereomeric salts obtained.

The compounds of formula I and their acid addition salts possess tachykinin receptor antagonistic properties and are therefore suitable for the treatment of diseases in larger mammals, especially humans, in which tachykinins are involved as mediators. The compounds of the invention are characterized by a particularly advantageous profile of action, which is characterized by a high selective affinity for the NK-2 receptor. Furthermore, the compounds according to the invention are distinguished by good tolerability and comparatively good oral availability even in the case of long-term use. Owing to their action profile, the compounds of the general formula I are particularly suitable for inhibiting processes in which NK-2 receptor-binding tachykinins, such as neurokinin A, are involved. Due to their action in a favourable way on the peripheral system, the compounds of general formula I are particularly suitable for the treatment and/or prevention of gastrointestinal functional and inflammatory diseases in larger mammals, in particular humans (both male and female), which are associated with increased pain sensitivity and/or disorders of stool passage in the colon segment. Functional disorders of the gastrointestinal tract treatable by the compounds of the present invention include, inter alia, lower bowel disorders known as "irritable bowel syndrome" (═ IBS) or irritable bowel syndrome. The diagnosis of the typical symptoms of IBS is described, for example, in W.G.Thompson et al, International gastroenterology 2 (1989) 92-95 or W.G.Thompson et al, GUT 45/II (1999) II43-II47, and is generally known in the industry as the "Rome criterion" concept. The main symptoms of IBS are lower abdominal pain, presumably due to hypersensitivity of the visceral afferent nervous system, and stool abnormalities such as constipation, diarrhea or alternating constipation and diarrhea. Other gastrointestinal inflammatory diseases which may be advantageously affected by the compounds of the invention are, for example, inflammatory diseases of the small and large intestine, which are generally referred to in most terms as "inflammatory bowel disease" (IBD), such as ulcerative colitis or Crohn's disease (Crohn's disease). Due to their mechanism of action, the compounds of the invention are also suitable for the treatment of other diseases in which tachykinins, in particular neurokinin a, are involved as mediators. These diseases include, for example, neurogenic inflammation, inflammatory joint diseases such as rheumatoid arthritis, asthmatic diseases, allergic diseases, immunoregulatory disorders, cystitis or functional dyspepsia.

Description of pharmacological test methods

The preparation examples described below are cited as the example numbers of the compounds of the general formula I to be used as test substances in the pharmacological tests described below.

1. In vitro assay for the binding Capacity of a test substance to NK-2-receptor

The affinity of the test substance for the human NK-2-receptor was determined in vitro. The ability of the test substance to displace the selective NK-2-receptor antagonist SR 48968 (Saredutant), which was used as a reference ligand, from its corresponding binding was determined.

Labeled with radioactivity³H]SR 48968 (Amersham) as ligand for receptor binding assays. For binding assays, various samples of membrane preparations of CHO-cells (Chinese hamster ovary cells), the human NK-2-receptor (prepared as described in N.P. Gerard et al, J. Biochem. 265/33 (1990) 20455-20462), were incubated for 90 minutes with a solution of labeled ligand, wherein the incubation component contained no test substance or was supplemented with different concentrations of test substance. Then the ligand bound to the membrane in the sample is filtered and dissociatedThe ligands are separated. The fraction remaining in the filter was washed several times with buffer and then its radioactivity was measured with a liquid scintillation counter. IC of each tested substance₅₀The concentration is the concentration at which it will bind the half-maximal displacement of the reference ligand. From a corresponding IC₅₀The values can be converted into the inhibition constant (Ki-value) of the test substance and expressed as its negative logarithm (pKi).

For the compounds of examples 1 to 39, at 10^-6To 10^-10The affinity of the test substance for the human NK-2 receptor was determined in the mol/L concentration series by measuring it at least three times. If there are more measurements, the average is given separately. In this test mode, all of the above test substances have pKi-values of at least 7.0. The compounds of examples 1 to 27 and 39 have a pKi-value of at least 8.0. The compounds of examples 1 to 6 and 39 have a pKi-value of at least 9.0.

2. In vitro assay for the functional antagonism of test substances on guinea pig isolated tissues

NK-2-receptor antagonism of test substances was determined on isolated specimens of the gallbladder of Pirbright-white guinea pigs kept in oxygen-saturated nutrient solution. For this purpose, one end of the specimen is fixed to an organ support in nutrient solution, and the other end is fixed to a force gauge with a thread.

In this test, the NK-2 receptor present in gallbladder specimens is stimulated with the natural NK-2 receptor potentiator neurokinin A (═ NKA; 0.1. mu. mol/L), and the resultant specimen contractions are measured and expressed as contractility in mM (═ prophase). NKA was then washed out of the specimen with NKA-free solution and added 10^-7Test substance at mol/L concentration. After incubation of the samples with the test substances for 2 hours, the contraction of the samples induced again by addition of NKA was determined again and the results expressed as a percentage of the contractile force induced by addition of NKA alone relative to the initial measurement. Repeatedly increasing the concentration of the test substance in the sequence test according to the results in logarithmic full-or semi-scale units until at least a concentration above or below 50% of the contraction-inhibiting effect is obtained (up to a maximum of 10)^-5mol/L). For each concentrationThe average of the contraction inhibition of 2 to 4 specimens was calculated. Calculating half maximal Inhibitory Concentration (IC) of each test substance₅₀) As characteristic parameters. The following description is of the IC of each test substance₅₀Logarithmic values, in pIC respectively₅₀And (4) showing. The test substances listed in table 1 below in this test mode have the pIC as specified below₅₀-a value.

TABLE 1: functional NK-2-antagonism of test substances on isolated guinea pig tissues

Example No. 2	pIC50
		1	9.8
7	9.6
		9	9.3
13	9.4
		14	8.7
17	9.7

In vivo assay for NK-2 receptor antagonism of test substances

Test substances were tested in vivo for NK-2-and NK-1-receptor antagonistic activity in anesthetized guinea pigs after intravenous (i.v.) and oral (p.o.) administration, respectively. By means of this test model, it was possible to observe both NK-2-antagonistic effects in three different organ systems (respiratory, colon and circulatory) and NK-1-antagonistic effects in animals (rapid lowering of blood pressure).

Pirbright-white guinea pigs weighing 500-. Animals were fitted with one intravenous catheter for administration of the test substance and another intra-arterial catheter for blood pressure measurement. Animals were artificially breathed through tracheal tubes and respiratory pressure was recorded by a manometer. To record the activity of the colon tonometrically by means of a pressure gauge, a balloon is inserted into the distal colon. Blood pressure, heart rate, respiratory pressure and colonic pressure were measured continuously on each animal and recorded on a recorder and by a digital data acquisition system. Neurokinin A (NKA; 200 pmol/animal) was injected intravenously by bolus injection for stimulation of NK-1-and NK-2-receptors. Such administration of NKA results in a significant increase in respiratory pressure (bronchoconstriction) and in colonic pressure, as well as a two-stage decrease in blood pressure. The first low pressure phase (the period of maximal hypotension within the first minute after NKA administration) is mediated by the NK-1-receptor, since it can be completely blocked by specific NK-1-receptor antagonists. The second, delayed onset, low pressure period (maximal hypotension period after 2-5 minutes) is mediated by the NK-2 receptor, since it can be blocked by specific NK-2 receptor antagonists. Characteristic values of these measured parameters as bronchoconstriction, colonic pressure and NK-1-and NK-2-mediated blood pressure changes, as ED₅₀A value representation, which means that the test substance at this dose leads to a reduction in the response to the test stimulus NKA to 50% of the initial value.

The test substances were first tested for antagonistic effect in an increasing manner, whereby the timing of the NKA-test stimulation was 1 minute after the end of the dosing of the respective dose of test substance. These ED's obtained from increasing dose-effect curves₅₀The values are recorded in table 2 below (row 1). To summarize the time course of the antagonistic effect of the test substance, the following isThe effect of NKA-test stimulation was determined at various times (1, 30, 60, 90, 120, 150 and 180 minutes) after administration of the test substances. The antagonistic effect of the test substance is then determined as the Area under the curve ("Area undercut", "AUC") over the test period after administration of the test substance (intravenous: 120 min after administration; oral: 180 min after administration), the ED thus obtained₅₀The values are listed in table 2 below (rows 2 and 3).

Table 2: in vivo testing of NK-2 receptor antagonism of test substances of formula I in guinea pigs

ED50	Parameter(s)	Example 1	Example 5	Example 13	Example 14	Example 15
							i.v.[μmol/kg]After 1 minute (increasing)	Colonic pressure	0.017	0.041	0.019	0.042	0.041
Resistance to breathing	0.033	0.106	0.048	0.078	0.079
						Blood pressure		0.025	0.130	0.080	0.063	0.114
i.v.[μmol/kg]AUC within 120 min	Colonic pressure	0.0009	0.014	0.018	--								0.009
						Resistance to breathing	0.008	0.008	0.023	--	0.042
	Blood pressure	0.006	0.004	0.025	--							0.047
						i.v.[μmol/kg]AUC within 180 min	Colonic pressure	0.5	3.4	1.9	3.2		4.5
Resistance to breathing	1.8	2.7	2.0	6.7	3.2
							Blood pressure	2.7	7.6	24	9.4	8.6

The measured values reported in table 2 above indicate that: the substances of examples 1, 5, 13, 14 and 15, after increasing intravenous administration (antagonism occurring 1 minute after the end of the administration of the test substance), caused significant NK-2-receptor antagonistic activity in colonic motility, late blood pressure decline and respiratory resistance.

The measured values reported in table 2 above also indicate: the above substances, especially the substance of example 1, have a more potent inhibitory effect on the NK-2-mechanism of the colon (colonic preference) compared to their NK-2-effects of inhibiting bronchoconstriction or lowering blood pressure. The compounds of the invention, especially the material of example 1, are also characterized by slow onset and long-lasting action.

No NK-1-receptor antagonism at the applied in vivo dose was observed for the tested test substances.

The compounds of formula I may be administered in the form of conventional pharmaceutical preparations. The dosage to be applied may vary from individual to individual and will of course vary depending on the type of disease state to be treated and the substance to be applied. Generally, suitable for administration to humans and larger mammals are also pharmaceutical preparations containing 0.2 to 200mg of active substance per single dose, in particular 1 to 50mg of active substance. The compounds of the present invention may be included in solid or liquid pharmaceutical formulations together with usual pharmaceutical adjuvants and/or carriers. Examples of solid preparations are orally administrable preparations such as tablets, dragees, capsules, powders or granules, but also suppositories. These preparations may contain, in addition to pharmaceutically customary adjuvants, such as lubricants or tablet disintegrants, pharmaceutically customary inorganic and/or organic carrier substances, such as talc, lactose or starch. Liquid formulations such as suspensions or emulsions of the active substance may contain conventional diluents such as water, oils and/or suspending agents such as polyethylene glycol and the like. Other adjuvants such as preservatives, flavoring agents, and the like may also be added.

The active substances can be mixed and formulated in accordance with known methods together with pharmaceutical adjuvants and/or carriers. For the preparation of solid pharmaceutical dosage forms, the active substances can be mixed, for example together with adjuvants and/or carriers, according to known methods and then granulated, wet or dry. Granules or powders may be directly filled into capsules or compressed into tablet cores according to known methods, which may be coated according to known methods if desired.

The following examples are presented to further illustrate the present invention but are not intended to limit the scope thereof.

Example 1：

N- [ (2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl ] -N-methylbenzamide

A) 45.0g N- [ ((2S) -2- (3, 4-dichlorophenyl) -4-methanesulfonyl-oxy) -N-methylbenzamide was dissolved in 550ml of acetone under a protective gas atmosphere. 84.6g of sodium iodide was added thereto, and the obtained suspension was stirred at room temperature for 20 hours. The solvent was substantially evaporated in vacuo and the remaining residue was taken up in 650ml methyl-tert-butyl ether (═ MTBE) and 500ml water. 120g of Na was added₂S₂O₄The aqueous phase is then separated and the remaining organic phase is washed four times with 100ml of saturated physiological saline each time. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo. The remaining residue was dried in vacuo to give 45.9g N- [ ((2S) -2- (3, 4-dichlorophenyl) -4-iodobutyl) -N-methylbenzamide]It is a glassy compound which can be used directly for further reactions without further purification.

B) 15.38g of 15.38g N-tert-butyloxycarbonyl-piperazine was dissolved in 200ml of toluene at room temperature under a protective gas atmosphere and mixed with 32ml of triethylamine. The resulting solution was heated to 84 ℃. 45.9g of the iodide obtained above dissolved in a mixture of 100ml of THF and 200ml of toluene were slowly added dropwise thereto. The reaction mixture thus obtained was heated at 80 to 85 ℃ for 5 hours, followed by stirring at room temperature for 8 hours. The solvent mixture was substantially evaporated in vacuo and the remaining residue was taken up in 600ml ethyl acetate (═ EE). After separation of the precipitate, the organic phase is washed twice with 100ml of water and 100ml of 15% aqueous tartaric acid, respectively, in that order. 8.0g of NaOH are then added to the organic phase and the mixture is washed twice with 200ml of water. The organic phase was dried over sodium sulfate and the solvent was evaporated in vacuo to give 44.9g of tert-butyl-4- [ (3S) -4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) -butyl ] -1-piperazinecarboxylate as an oily compound which was used directly for further reaction without further purification.

C) 44.5g of the piperazine carboxylate compound obtained above was dissolved in 600ml of methanol at room temperature, mixed with 150ml of 6N HCl, and stirred for 60 hours. Subsequently 500ml of water are added and the methanol phase is substantially evaporated in vacuo. The remaining aqueous phase was extracted 4 times with 100ml of EE each time and 4 times with 100ml of MTBE each time. A solution of 36.0g of sodium hydroxide in 200ml of water is then added to the aqueous phase and the aqueous alkaline solution is extracted 2 times each time with 350ml of EE. The combined organic phases are washed with 100ml of water, dried over sodium sulfate and evaporated in vacuo. The residue was dried to give 25.8g N- [ (2S) -2- (3, 4-dichlorophenyl) -4- (piperazinyl) butyl ] -N-methylbenzamide as a pale yellow solid oil which was used for further reaction without further purification.

D) 25.0g of the deprotected piperazine compound obtained above are dissolved in 250ml of ethanol at 30 ℃ under a protective gas atmosphere. After heating it to 50 to 60 ℃, 10.0g of thiophene-3-boronic acid was added first, followed by 8.93g D-xylose. The mixture was boiled under reflux cooling for 15 hours, followed by stirring at room temperature for 8 hours. 500ml of water are added and the solvent mixture is evaporated essentially in vacuo. To the remaining residue was added 20ml of 6N hydrochloric acid and washed sequentially first 1 time with 200ml of EE and then 6 times with 100ml of EE each time. The aqueous phase is adjusted to a pH of 9-10 by addition of the corresponding dose of 4N sodium hydroxide and then extracted with 600ml of dichloromethane. The organic phase was separated, dried over sodium sulfate and then evaporated in vacuo. 32.0g of the title compound are obtained as an amorphous solid substance with an optical rotation [ alpha ]]_D ²⁰-14.8(c ═ 1 in methanol);¹H-NMR(d₆-DMSO，90℃)：3,81(d，1H)；4,15(dd，1H)；3,79(dd，1H)；3,66(ddd，1H)；3,48(m，2H)；7,12(dd，1H)；7,19(d，1H)；7,38(dd，1H).

example 2：

N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl ] -1-piperazinyl } butyl) -N-methylbenzamide

2.08g N- [ (2S) -2- (3, 4-dichlorophenyl) -4- (piperazinyl) butyl]-N-methylbenzamide (preparation see 1C above) was dissolved in 100ml of ethanol and heated to about 50 ℃. 740mg of 2-furanboronic acid and 550mg of 80% D-glyceraldehyde solution in water were added thereto. The resulting solution was boiled under reflux for 10 hours. The excess solvent was then evaporated in vacuo. The residue was purified by silica gel column chromatography (developing solvent: dichloromethane/EtOH/NH)₄OH 87/11/2) to yield 2.1g of the title compound as a beige foam having an optical rotation value [ alpha ]]_D ²⁰-6.1 ° (c ═ 1 in methanol);

¹H-NMR(CDCl₃，RT)：3,65(d，1H)；4,23(ddd，1H)；3,72(dd，1H)；3,78(dd，1H)；6,27(d，1H)；6,37(1H)；7,42(1H).

example 3：

(2S) -2- (acetyloxy) -3- {4- [ (3S) -4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] -1-piperazinyl } -3- (2-furyl) propyl-acetate

To a solution of 400mg of N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl]-1-piperazinyl } butyl) -N-methylbenzamide (prepared as in example 2) in 10ml of pyridine was added at room temperature with 1.5g of acetic anhydride. The reaction mixture was stirred for 72 hours, followed by the injection of 2.2g Na₂CO₃In a solution of 40ml of water. The organic phase is extracted with 60ml of toluene and the toluene phase is washed 3 times with 30ml of water each time and 2 times with saturated physiological saline solution each time. The combined organic phases were dried over sodium sulfate and the solvent was evaporated in vacuo. 463mg of the title compound are obtained as a yellow foam, [ alpha ]]_D ²⁰+9.6 ° (c ═ 1 in methanol);¹H-NMR(CDCl₃，RT)：3,81(d，1H)；5,62(ddd，1H)；4,58(dd，1H)；4,21(dd，1H)；1,87(s，3H)；2,05(s，3H)；6,16(d，1H)；6,31(1H)；7,35(1H).

example 4：

N- ((2S) -2- (3, 4-dichlorophenyl) -4- (4- { 2-furyl [ (4S) -2-oxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) butyl) -N-methylbenzamide

To 576mg of N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl]A solution of-1-piperazinyl } butyl) -N-methylbenzamide (prepared as in example 2) in 30ml of dry dichloromethane was added at room temperature with 124mg of 4-dimethylaminopyridine (═ DMAP) and 410mg of N-carbonyldiimidazole. The reaction mixture was stirred at room temperature for 15 hours and then 3.7g of silica gel were added. The resulting suspension was further stirred for 1 hour, the liquid phase was separated by vacuum filtration, and the filtrate was concentrated in vacuo. The remaining residue was taken up in 50ml of EE and the organic phase was washed once with 5% KH₂PO₄Aqueous solution and 1% K₂HPO₄10ml of a 50: 50 mixture of aqueous solutions were washed 5 times. The organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo. 460mg of the title compound are obtained as a white foam,¹H-NMR(CDCl₃，RT)：3,73(d，1H)；5,07(ddd，1H)；4,56(dd，1H)；4,48(dd，1H)；6.3(d，1H)；6,378(1H)；7,41(1H).

the title compound obtained was dissolved in 4M1 methanol and 0.31ml 1.6M HCl in isopropanol was added. To give the dihydrochloride of the title compound, [ alpha ]]_D ²⁰-28 ° (c ═ 1 in methanol).

The compounds of the general formula I listed in Table 3 below can also be prepared by the methods described in the above examples or analogously thereto.

The compounds of examples 5-38 listed in table 3 below were prepared according to an automated procedure. For each batch, 200. mu.l of a 0.25N aqueous stock solution of the corresponding carbohydrate of the formula IV are metered in to the microreaction vessel and evaporated in vacuo to remove substantially the water. The residue was taken up in 200. mu.l ethanol. To this was added 200. mu.l of 0.25mol, respectivelyL racemic or enantiomerically pure N- [2- (3, 4-dichlorophenyl) -4- (1-piperazinyl) -butyl ] of the formula II (cf. table 3)]-an ethanol stock solution of N-methylbenzamide, and 200 μ l of a 0.25N ethanol stock solution of the corresponding boronic acid of formula III (═ dihydroxyborane-compound). The reaction mixture was first heated at 80 ℃ for 2 hours, then cooled to room temperature and mixed with 1ml ethanol. Followed by addition of 100mg of basic Amberjet^Ion exchange resin and shaking the reaction vessel for 2 hours. The ion exchanger was filtered off, washed 2 times with 500. mu.l of ethanol each time, and the solvent was evaporated in vacuo to dryness. Samples were taken from the residue without further purification, for high performance liquid chromatography (═ HPLC), and for automated mass spectrometry to determine purity, or for structure determination, respectively.

Table 3:other compounds of the formula I

Examples	A	Z													Configuration(s)*C	Salt (salt)	MS[m/z]
																		R1	R2	R3	R4	R5	k	l	m	n	Configuration(s)
		CR1	CR2	CR3	CR4
						5	3-thienyl radical	H	--	--	--	H	1	0													0	0	S	--	--	--	S	Alkali	576
6	3-furyl radical	H	--	--	--										H	1	0	0	0	S	--	--	--	S	Alkali	560
						7	3-thienyl radical	H	H	H	--	H	1	1													1	0	S	R	R	--	RS	2TF	636
8	3-thienyl radical	H	--	--	--										H	1	0	0	0	S	--	--	--	RS	Alkali	576
						9	3-thienyl radical	H	H	H	--	H	1	1													1	0	R	R	R	--	RS	2TF	636
10	2-furyl radical	H	H	H	--										H	1	1	1	0	S	R	R	--	S	Alkali	620
						11	3-thienyl radical	H	--	--	--	H	1	0													0	0	R	--	--	--	RS	Alkali	576
12	3-thienyl radical	H	H	H	--										H	1	1	1	0	R	S	S	--	S	Alkali	636
						13	2-furyl radical	H	H	H	--	H	1	1													1	0	S	R	R	--	RS	2Cl	620
14	3-thienyl radical	Acetyl group	Acetyl group	Acetyl group	--										Acetyl group	1	1	1	0	S	R	R	--	S	Alkali	804
						15	3-thienyl radical	H	H	--	--	H	1	1													0	0	S	R	--	--	S	Alkali	606
16	3-thienyl radical	H	H	--	--										H	1	1	0	0	S	S	--	--	RS	Alkali	606
						17	3-thienyl radical	H	H	H	--	H	1	1													1	0	R	S	R	--	RS	2TF	636
18	3-thienyl radical	H	--	--	--										H	1	0	0	0	RS	--	--	--	RS	2TF	576
						19	2-thienyl radical	H	H	H	--	H	1	1													1	0	R	S	R	--	RS	2TF	636
20	3-thienyl radical	H	H	H	H										H	1	1	1	1	R	S	S	S	RS	2TF	666
						21	3-thienyl radical	H	H	H	H	H	1	1													1	1	R	R	R	R	RS	2TF	666

TF ═ trifluoroacetate; MS mass spectrum

Table 3:other compounds of the formula I (continuation)

Examples	A	Z													Configuration(s)*C	Salt (salt)	MS[m/z]
																		R1	R2	R3	R4	R5	k	l	m	n	Configuration(s)
		CR1	CR2	CR3	CR4
						22	2-thienyl radical	H	--	--	--	H	1	0													0	0	RS	--	--	--	RS	2Cl	576
23	3-thienyl radical	H	H	H	H										H	1	1	1	1	S	R	R	R	RS	Alkali	666
						24	2-thienyl radical	H	H	H	--	H	1	1													1	0	S	R	R	--	RS	2TF	*
25	Phenyl radical	H	H	H	--										H	1	1	1	0	S	R	R	--	RS	Alkali	630
						26	3-thienyl radical	--	--	--	--	H	0	0													0	0	--	--	--	--	RS	Alkali	546
27	3-thienyl radical	H	H	H	--										H	1	1	1	0	R	R	S	--	RS	Alkali	636
						28	3-thienyl radical	H	H	--	--	H	1	1													0	0	S	R	--	--	RS	Alkali	606
29	1-hexenyl	H	H	H	--										H	1	1	1	0	R	S	R	--	RS	Alkali	636
						30	2-furyl radical	H	H	H	--	H	1	1													1	0	S	R	S	--	RS	2Cl	620
31	1- (4-phenyl) butenyl	H	H	H	--										H	1	1	1	0	R	S	R	--	RS	Alkali	684
						32	4-methoxyphenyl radical	H	--	--	--	H	1	0													0	0	S	--	--	--	S	Alkali	600
33	1- (4-phenyl) butenyl	H	H	H	--										H	1	1	1	0	S	R	R	--	RS	Alkali	684
						34	3-thienyl radical	H	H	H	H	H	1	1													1	1	S	R	S	R	RS	Alkali	666
35	3-thienyl radical	H	H	H	H										H	1	1	1	1	S	S	R	R	RS	Alkali	666
						36	1- (4-phenyl) butenyl	H	H	H	--	H	1	1													1	0	R	R	R	--	RS	Alkali	684
37	5-indolyl radical	H	H	H	--										H	1	1	1	0	S	R	R	--	RS	2Cl	**
						38	2-naphthyl radical	H	--	--	--	H	1	0													0	0	RS	--	--	--	RS	Alkali	620

TF ═ trifluoroacetate; MS mass spectrum

Example 24 Compounds in¹H-NMR-Spectroscopy (CD)₃OD) had the following values: δ — 3.95 (d); 4.20 (d);

example 24 Compound in¹H-NMR-Spectroscopy (CD)₃OD) had the following values: δ 4.59 (b); 6.95 (b); 7.19 (b); 7.51 (d); 7.92 (b).

Example 39：

N- ((2S) -2- (3, 4-dichlorophenyl) -4- { 2-furyl [ (4S) -2-thioxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) -butyl) -N-methylbenzamide

To 303mg of N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl]A solution of-1-piperazinyl } butyl) -N-methylbenzamide (prepared as described in example 2) in 10ml of dry dichloromethane was added 240mg of N, N' -thiocarbonyldiimidazole at room temperature. The reaction mixture was stirred at room temperature for 20 hours, then concentrated in a water jet pump vacuum. The remaining residue was taken up in 50ml of EE and the organic phase was washed 5 times with water. The organic phase was dried over sodium sulfate and the solvent was then evaporated in vacuo (first water jet pump, then oil pump). The pale yellow foam column obtained was purified by chromatography (stationary phase: silica gel; mobile phase: n-hexane/acetone 1: 1) to give 118mg of the amorphous title compound,¹H-NMR(CDCl₃，RT)：3.79(d，1H)；5.10(ddd，1H)；6.27(1H)；6.36(1H)。

example I:

capsules containing N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl) -N-methylbenzamide:

each capsule was prepared according to the following composition:

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl) -N-methylbenzamide 20mg

Corn starch 60mg

Lactose 300mg

Proper amount of ethyl acetate

The active substance, corn starch and lactose were processed into a homogeneous pasty mixture by adding EE. The paste was chopped and the granules formed were filled into suitable trays and dried at 45 ℃ to remove the solvent. The dried granules were crushed by a crusher and then mixed in a mixer with the following other adjuvants:

talcum powder 5mg

Magnesium stearate 5mg

Corn starch 9mg

And then filled into 400mg capacity capsules (═ capsule size 0).

Claims (11)

1. A compound of the general formula I

Wherein

A represents naphthyl, phenyl optionally substituted by hydroxy, mono-or bicyclic heteroaryl or C optionally substituted by phenyl_3-6-an alkenyl group,

z is a group of the formula

A group of (1), wherein

R¹Is hydrogen or C_2-4-alkanoyl or with a group selected from R²、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R²represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R³represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁴represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R³And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁵represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R³And R⁴Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

k represents a number of 0 or 1,

l represents a number of 0 or 1,

m represents 0 or 1, and

n represents a number of 0 or 1,

R⁶represents halogen or hydrogen and

R⁷represents a halogen or a hydrogen atom, or a salt thereof,

and physiologically tolerated acid addition salts of the compounds of the general formula I.

2. A compound according to claim 1, wherein a is thiophene or furan.

3. A compound according to claim 1, wherein k is 1 and n is 0.

4. A compound according to claim 1, wherein R is⁶And R⁷Respectively chlorine.

5. A compound according to claim 1 wherein the chiral center^*C has the S-configuration.

6. A compound of the formula I according to one of the preceding claims, selected from the following group of compounds

N- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4- [ (2S) -2, 3-dihydroxy-1- (2-furyl) propyl ] -1-piperazinyl } butyl) -N-methylbenzamide;

(2S) -2- (acetyloxy) -3- {4- [ (3S) -4- [ benzoyl (methyl) amino ] -3- (3, 4-dichlorophenyl) butyl ] -1-piperazinyl } -3- (2-furyl) propyl-acetate;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- (4- { 2-furyl [ (4S) -2-oxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (1S, 2R) -2, 3-dihydroxy-1- (3-thienyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S) -2, 3-dihydroxy-1- (3-furyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxy-1- (2-furyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R) -2, 3-dihydroxy-1- (3-thienyl) propyl ] -1-piperazinyl } -butyl-N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2R, 3S, 4S) -2, 3, 4, 5-tetrahydroxy-1- (3-thienyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R, 4R) -2, 3, 4, 5-tetrahydroxyacetyl-1- (3-thienyl) pentyl ] -1-piperazinyl } -butyl) -N-methylbenzamide;

n- ((2S) -2- (3, 4-dichlorophenyl) -4- {4[ (2S, 3R) -2, 3, 4-trihydroxy-1- (3-thienyl) butyl ] -1-piperazinyl } -butyl) -N-methylbenzamide and

n- ((2S) -2- (3, 4-dichlorophenyl) -4- { 2-furyl [ (4S) -2-thioxo-1, 3-dioxolan-4-yl ] methyl } -1-piperazinyl) -butyl) -N-methylbenzamide.

7. A medicament containing a pharmacologically active dose of a compound according to claim 1 and customary pharmaceutical adjuvants and/or carriers.

8. Use of a compound according to claim 1 for the preparation of a pharmaceutical preparation for the treatment and/or prophylaxis of functional or inflammatory disorders of the lower intestinal tract in mammals and humans which are associated with an increased sensitivity to pain in the colonic region and/or a disturbed passage of faeces.

9. The use according to claim 8, wherein the disorder is irritable bowel syndrome.

10. A process for the preparation of compounds of the general formula I and their physiologically tolerated acid addition salts,

wherein

A represents naphthyl, phenyl optionally substituted by hydroxy, mono-or bicyclic heteroaryl or C optionally substituted by phenyl_3-6-an alkenyl group,

z is a group of the formula

A group of (1), wherein

R¹Is hydrogen or C_2-4-alkanoyl or with a group selected from R²、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R²represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R³、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R³represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R⁴And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁴represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R³And R⁵Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

R⁵represents hydrogen or C_2-4-alkanoyl or with a group selected from R¹、R²、R³And R⁴Together with another substituent(s) forming a through carbonyl, thiocarbonyl or through an optionally substituted C_1-4-alkyl or C_4-5An alkylene-substituted methylene-bridged 5-or 6-membered ring,

k represents a number of 0 or 1,

l represents a number of 0 or 1,

m represents 0 or 1 and

n represents a number of 0 or 1,

R⁶represents halogen or hydrogen and

R⁷represents a halogen or a hydrogen atom, or a salt thereof,

characterized in that a compound of the general formula II

Wherein R is⁶And R⁷As defined above, with the compounds of the general formula III,

A-B(OH)₂ III

wherein A is as defined above, and with a compound of the general formula IV,

wherein R is¹、R²、R³、R⁴、R⁵K, l, m and n are as defined above, and then, if desired, reacting the obtained compound of the formula I, wherein at least one is selected from R¹、R²、R³、R⁴And R⁵The substituent(s) represents hydrogen, by reaction with a compound of formula VIII,

R⁸-COOH (VIII)

wherein R is⁸Denotes a straight-chain or branched alkyl radical having 1 to 3 carbon atoms, acylated in the radical Z or followed, if desired, by the compound of the formula I obtained, at least two of which are selected from R¹、R²、R³、R⁴And R⁵The substituents of (A) represent hydrogen, byCarbonylating or thiocarbonylating in a group Z with a reactive carbonyl-or thiocarbonyl-synthesis equivalent, or else reacting the compounds of the general formula I obtained, at least two of which are selected from R¹、R²、R³、R⁴And R⁵The substituent(s) represents hydrogen by reaction with a di-C_1-4-alkyl ketone or a C_5-6-conversion of a cycloalkyl ketone into an optionally substituted C in the group Z by reaction_1-4-alkyl or C_4-5-5-or 6-membered ring-derivatives bridged by an alkylene-substituted methylene group, and, if desired, converting the obtained compounds of the general formula I into their acid addition salts or converting the acid addition salts into the free compounds of the general formula I.

11. A compound of the general formula II,

wherein

R⁶Represents halogen or hydrogen and

R⁷represents halogen or hydrogen.