MXPA00000615A - Piperazine derivatives - Google Patents

Abstract

The invention relates to piperazine derivatives of formula (I), wherein R1, m, k and R2 have the meaning given in Claim 1. Said piperazine derivatives are potent 5-HT1A agonists, have 5-HT-re-uptake inhibiting effects and are suitable for treating and preventing anxiety states, depression, schizophrenia, obsessive thoughts, tardive dyskensia, learning impairments and memory disturbances caused by age, for positively influencing compulsive behaviour, and for treating and combating the effects of cerebral infarctions, such as strokes and cerebral ischaemia.

Description

DERIVATIVES OF PIPERAZINE DESCRIPTION OF THE INVENTION The invention relates to the piperazine derivatives of the formula I wherein R1 represents an indole-3-yl moiety unsubstituted or mono- or di-substituted with Hal, CN, A, AO, OH, CONH2, CONHA, CONA2, COOH, COOA, CH2OH, CH2OA, CH2NH2, CH2NHA and / or CH2NA2, R2 represents 2-oxo-2H-l-benzopyran-6-yl or 2-oxo-2H-benzopyran-4-yl unsubstituted or mono- or di-substituted with A, AO, OH, Hal, CN, N02, NH2, NHA, NA2, COA, CONH2, CONHA, C0NA2, CH2OH, CH2OA, CH2NH2, CH2NHA, CH2NA2, COOH and / or COOA, Hal represents F, Cl, Br or I, A represents straight or branched chain alkyl with 1 to 10 C atoms and which may be substituted with 1 to 5 F atoms and / or Cl, or cycloalkyl of 3 to 10 C atoms, REF .: 32268 m is 2, 3 or 4, and its salts acceptable from the physiological point of view. The aim of the invention was to develop new compounds with valuable properties, in particular compounds that can be used in the manufacture of medicines. It was found that the compounds of formula I and their acid addition salts, which are physiologically acceptable, possess particularly valuable pharmacological properties. The compounds of formula I influence the serotonergic transmission. These compounds are particularly suitable for use as antidepressants and anxiolytics, they can also inhibit the reuptake of serotonin. They exhibit properties of serotonin agonists and antagonists. They inhibit the binding of tritiated serotonin ligands to hippocampal receptors (Cossery et al., European J. Pharmacol 140 (1987), pages 143-155) and inhibit serotonin reuptake (Sherman et al., Life, Sci. 2_3 (1978), pp. 1863-1870). In addition, modifications occur in the accumulation of DOPA in the striatum and 5-HT in different regions of the brain (Seyfried et al., European J. Pharmacol., 160 (1989), pp. 31-41). The 5-HTαA antagonist action is tested in vi tro, for example, by inhibiting the nullification of the electrically induced concentration that causes 8-OH-DPAT in the coballous ileum (Fozard and Kilbinger, Br. J. Pharmacol 86 (1985) 601P). The inhibition of reduced 5-HTP accumulation by 8-OH-DPAT (Seyfried et al., European J. Pharmacol., 160 (1989), pp. 31-41) and the antagonism of the effects induced by 8-OH- DPAT in the ultrasound vocalization assay (DeVry, Psychopharmacol 121 (1995), pp. 1-26) serve for the in vi ve verification of the 5-HTIA antagonist action. The inhibition of serotonin reuptake serves as synaptic inhibition of absorption (ong et al., Nauropsychopharmacol., 8 (1993), pp. 23-33) and antagonism of p-chloroamphetamine (Fuller et al. ., J. Pharmacol. Exp. Ther. 212 (1980), pp. 115-119). There are also analgesic and hypotensive effects. Therefore, the compounds are suitable for the treatment of schizophrenia, cognitive deficit, fear, depression, stomach discomfort, tardive dyskinesia, gastrointestinal disorders, learning disorders, senile disorders of memory, psychoses, and to exert a positive influence on obsessive behaviors (OCD) and eating disorders (for example, bulimia). These compounds affect the central nervous system, in particular, have a 5-HT1A-agonist action and inhibit the reabsorption of 5-HT. They can also be used for the prophylaxis of and the fight against the sequelae of a cerebral infarction (apoplexy cerebri) such as a stroke attack and cerebral ischemia, as well as for the treatment of secondary motor-extrapyramidal effects of neuroleptics and for the treatment of Morbus Parkinson. Therefore, the compounds of formula I are suitable both in veterinary medicine and in medicine for the treatment of functional disorders of the central nervous system and also of inflammations. They can be used for the prophylaxis of and the fight against the sequelae of a cerebral infarct (apoplexia cerebri) such as a stroke attack and cerebral ischaemia., as well as for the treatment of secondary motor-extrapyramidal effects of neuroleptics and for the treatment of Morbus Parkinson, for the acute and symptomatic therapy of Alzheimer's disease and for the treatment of amyotrophic lateral sclerosis. They are also suitable as therapeutic substances for the treatment of brain and spinal cord injuries. However, they are particularly suitable for use as anxiolytics, antidepressants, antipsychotics, neuroleptics, antihypertensive agents and / or to exert a positive influence on obsessive behaviors, sleep disorders, tardive dyskinesia, learning disorders, Senile disorders of memory, eating disorders such as bulimia and / or disorders of sexual function. Therefore, the derivatives of the piperazine of formula I and their physiologically acceptable acid addition salts are subject of the present invention. In particular, the compounds of formula I chosen from the group consisting of a) 3- are the subject of the invention. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -indol-5-carbonitrile; b) 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -5-fluoro-indole; c) 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1- piperazinyl] -butyl} -indole-5-carbonitrile; d) 3-. { 4- [4- (7-hydroxy-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -indole-5-carbonitrile; and the physiologically acceptable salts of these compounds. The meanings of all the remains that appear repeatedly, such as A, are independent of each other. The radical A represents alkyl and has from 1 to 10, preferably 1, 2, 3, 4, 5 or 6, and in particular, 1 or 2 carbon atoms. Therefore, the alkyl radical represents, in particular, example methyl, then ethyl, n-propyl, isopropyl, n-butyl, sec-butyl or terbutyl, then also pentyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2- or 2, 2- dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3, 3- dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, then also fluoromethyl, difluoromethyl, trifluoromethyl, 1,1,1-trichloroethyl or pentafluoroethyl. Cycloalkyl represents, in particular, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or 1-adamantyl. OA preferably represents methoxy, then also ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or terbutoxy. NHA preferably represents ethylamino, then ethylamino, isopropylamino, n-butylamino, isobutylamino, sec-butylamino or terbutylamino. NA2 preferably represents dimethylamino, then N-ethyl-N-methyl-amino, diethylamino, di-n-propylamino, diisopropylamino or di-n-butylamino. Accordingly, CO-NHA preferably represents N-methylcarbamoyl or N-ethylcarbamoyl; C0-NA2 preferably represents N, N-dimethylcarbamoyl or N, N-diethylcarbamoyl. Hal represents fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. k is 0 or 1, preferably 0. m is 1, 2, 3 or 4, preferably 3 or 4. The radical R 1 preferably represents 3-indolyl unsubstituted or mono- or disubstituted, preferably monosubstituted with. Hal, CN, A, AO, OH, CONH2, CONHA, CONA2, COOH, COOA, CH2OH, CH20A, CH2NH2, CH2NHA and / or CH2NA2. The rest of indole is preferably substituted in the 5-position, and also in the 6 -6-position. Therefore, R 1 preferably represents 2-or 3-indolyl, 5- or 6-methyl-indol-2-yl, 5- or 6-methyl-indol-3-yl, 5- or 6-methoxy-indol-2-yl, 5- or 6-methoxy-indol-3-yl, 5- or 6-hydroxy-indol-2-yl, - or 6-hydroxy-indol-3-yl, 5- or 6-fluoro-indol-2-yl, 5- or 6-fluoro-indol-3-yl, 5- or 6-cyano-indol-2-yl , 5- or 6-cyano-indol-3-yl, 5- or 6-chloro-indol-2-yl, 5- or 6-chloro-indol-3-yl, 5- or 6-carboxy-indole-2 -yl, 5- or 6-carboxy-indol-3-yl, 5- or 6-methoxycarbonyl-indol-2-yl, 5- or 6-methoxycarbonyl-indol-3-yl, 5- or 6-hydroxymethyl-indole -2-yl, 5- or 6-hydroxymethyl-indol-3-yl, 5- or 6-aminomethyl-indol-2-yl, 5- or 6-aminomethyl-indol-3-yl, then 5- or 6- bromo-indol-2-yl, 5- or 6-bromo-indol-3-yl, 5- or 6-ethyl-indol-2-yl, 5- or 6-ethyl-indol-3-yl, 5- or 6-trifluoromethyl-indol-2-yl, 5- or 6-trifluoromethyl-indol-3-yl, 5- or 6-isopropyl-indol-2-yl, 5- or 6-isopropyl-indo l-3-yl, 5- or 6-dimethylamino-indol-3-yl or 5- or 6-dimethylamino-indol-2-yl, 5- or 6-ethoxy-indol-3-yl or 5- or 6- ethoxy-indol-2-yl. The radical R2 preferably represents 2-oxo-2H-l-benzopyran-6-yl or 2-oxo-2H-l-benzopyran-4-yl unsubstituted or monosubstituted with A, AO, OH, Hal, CN, N02, NH2 , NHA, NA2, COA, CONH2, CONHA, CONA2, CH20H, CH20A, CH2NH2, CH2NHA, CH2NA2, COOH and / or COOA. Preferred substituents are A, AO, OH, Hal, CN, NH2 / NHA, NA2 and also CH2OH. Therefore, R2 preferably represents 2-oxo-2H-l-benzopyran-6-yl or 2-oxo-2H-l-benzopyran-4-yl, 7-hydroxy-2-oxo-2H-l-benzopyran-6 -yl, 7-hydroxy-2-oxo-2H-l-benzopyran-4-yl, 7-fluoro-2-oxo-2H-l-benzopyran-6-yl, 7-fluoro-2-oxo-2H-l -benzopyran-4-yl, 5-fluoro-2-oxo-2H-l-benzopyran-6-yl, 6-fluoro-2-oxo-2H-l-benzopyran-4-yl, 5-methyl-2-oxo -2H-l-benzopyran-4-yl, 7-methyl-2-oxo-2H-l-benzopyran-6-yl, 7-dimethylamino-2-oxo-2H-l-benzopyran-6-yl, 7-hydroxy -methyl-2-oxo-2H-l-benzopyran-6-yl or also 7-chloro-2-oxo-2H-l-benzopyran-6-yl. The residues defined by the invention that appear repeatedly in a molecule can be the same or different, that is, they are independent of each other. Accordingly, a particular object of the invention are those compounds of formula I in which at least one of the mentioned moieties has one of the preferred meanings indicated above. Some preferred groups of compounds can be represented by the formulas a to Ij indicated below, which correspond to formula I and in which the moieties which are not expressly detailed have the meaning indicated for formula I, viz. Ra represents unsubstituted 3-indolyl; in Ib R1 represents 3-indolyl substituted in position 5; in le k is 0 and m is 4; in Id k is 1 and m is 3; in R 1 it has the meaning indicated in Ib and the substituent Hal is, methoxycarbonyl, CN or carboxy; in If R2 represents 2-oxo-2H-l-benzopyran-6-yl; in Ig R2 represents 2-oxo-2H-l-benzopyran-4-yl; in Ih R2 it has the meaning indicated in If, but in position 7 it presents another substituent; in Ii R2 it has the meaning indicated in Ig, but in position 7 it carries another substituent; in Ij R2 has one of the meanings indicated in Ih or Ii, and the substituent is Hal or OH. Another object of the invention is a process for preparing the piperazine derivatives of formula I and their salts, characterized in that a compound of formula II is reacted HN N-FT II wherein R2 has the indicated meaning, with a compound of formula III R1- (CH2) m- (CO)? - L III where L represents Cl, Br, I, OH, OCOA, OCOPh, OS02A, OS02Ar, where Ar is phenyl or tolyl and A alkyl, or represents another esterified and reactive OH group or leaving group easily replaceable by a nucleophile and R1, myk have the meaning indicated above, or a compound of the invention is reacted by reductive amination. formula IV R1 - (CE2) m-1 - CEO IV wherein R1 and m have the meaning indicated above, with a compound of formula II, or because a compound is treated which responds to formula I, but which in the place of one or more hydrogen atoms contains one or more reducible groups and / or one or more additional CC and / or CN bonds, with a reducing agent, or by treating a compound that responds to formula I, but which in the place of one or several hydrogen atoms contains one or more solvolizable groups, with a solvolizing agent, and / or because a radical R1 and / or R2 is optionally converted to another radical R1 and / or R2, for example, by cleaving an OA group to form an OH group and / or derivatizing a CN group, COOH or COOA and / or by alkylating, for example, a primary or secondary nitrogen atom and / or converting a base or an acid of formula I, thus obtained, into one of its salts by treatment with an acid or one base. In general, the compounds of formula I are prepared according to methods known per se as is. they describe in the literature (for example, in certain works such as Houben-eyl's, "Methoden der organischen Chemie" (Methods of Organic Chemistry), Gorg-Thieme-Verlag, Stuttgart, "Organic Reactions", John iley &Sons, Inc., New York, and in the published, unexamined, German patent application No. 4,101,686), and under reaction conditions that are known and suitable for these reactions. You can also make use of known variants of these methods, but they are not detailed in this text. If desired, the starting materials for the claimed process can also be prepared in si t u, but in such a way that instead of isolating them from the reaction mixture they are directly reacted to form the compounds of formula I.

The residues L, X1 and X2 of the formulas III, V and VI preferably represent Cl or Br; they can also represent I, OH or preferably an OH group functionally transformed in a reactive group, in particular, a group of alkylsulfonyloxy of 1 to 6 C atoms (for example, methanesulfonyloxy) or of arylsulfonyloxy of 6 to 10 C atoms ( for example, benzenesulfonyloxy, p-toluenesulfonyloxy, 1- or 2-naphthalenesulfonyloxy). In general, the compounds of formulas II and III are known; the unknown compounds of formulas II and III can be prepared easily analogously to the known compounds. The majority of the piperazine derivatives of formula II are known. If they are not known or can not be obtained in stores, they can be prepared using methods known per se. They can be prepared, for example, by reaction of bis- (2-chloroethyl) -amine or bis- (2-chloroethyl) -ammonium chloride with benzopyran compounds substituted with amino. The indole derivatives of formula III are usually known and in most cases can be purchased in stores. They can also be prepared from known compounds by electrophilic substitution or, in certain cases, by aromatic nucleophilic substitution. As starting material, a suitable indole-3-alkanoic acid (obtained according to Fischer's indole synthesis, Japp-Klingemann type, see Bottcher et al., J. Med. Chem. 1992, 35, is preferably used). pp. 4020 to 4026 or lyer et al., J. Chem. Soc. Perkin Trans. II 1973, pp. 872 to 878). The primary alcohols of the formula R1- (CH2) m-0H are obtained, for example, by reduction of the corresponding carboxylic acids or their esters. The corresponding halides of the formula R2- (CH2) m-Hal are obtained by treatment with thionyl chloride, hydrogen bromide, phosphorus tribromide or similar halogenated compounds. The corresponding sulfonyloxy compounds are obtained from the alcohols by reaction with the corresponding sulfonyl chlorides. Iodine compounds of formula R1- (CH2) m are obtained, for example, by the action of potassium iodide on the corresponding p-toluenesulfonic esters. The amines of the formula R1- (CH2) m-NH2 are prepared, for example, by reaction of the halides with potassium phthalimide or by reduction of the corresponding nitriles. The reaction of the compounds II and III proceeds according to methods such as those known from the literature for the alkylation or acylation of amines. In the absence of a solvent, the components can be fused together optionally in a sealed tube or in an autoclave. However, it is also possible to react the compounds in the presence of an inert solvent. Suitable solvents include, for example, hydrocarbons such as benzene, toluene or xylene; ketones such as acetone or butanone; alcohols such as methanol, ethanol, isopropanol or n-butanol; ethers such as tetrahydrofuran (THF) or dioxane; amides such as dimethylformamide (DMF) or N-methylpyrrolidione; nitriles such as acetonitrile or possibly also mixtures of these solvents with each other or mixtures with water. It is sometimes convenient to add an acid trapping agent, for example a hydroxide, carbonate or bicarbonate of an alkali metal or alkaline earth metal or other salt of a weak acid and an alkali metal or alkaline earth metal, preferably a potassium, sodium or calcium salt, or adding an organic base such as triethylamine, dimethylaniline, pyridine or quinoline, or an excess of the derivative can be of some minutes and up to 14 days, depending on the conditions employed, and the reaction temperatures are between 0 and 150 ° C, generally between 20 and 130 ° C. Before carrying out this reaction, there may be a need to protect other present amino groups from an eventual alkylation or acylation by the incorporation of suitable protecting groups. The term "amino protecting group" is widely known and refers to those groups that are adapted to protect an amino group from chemical reactions and that are easily removed once the desired chemical reaction has been carried out elsewhere. of the molecule. Considering that the technician in the field has already resorted to a large number of publications and textbooks to know such protective groups and also the techniques of incorporation and removal thereof, no details on this subject will be included in the present text. The compounds of formula I can also be obtained by reductive amination of compounds of formula IV and reaction with compounds of formula II. The starting compounds of formula IV and II are usually known. If not, they can be obtained using methods known per se. The reductive amination can be carried out in the presence of a reducing agent such as, for example, NaBH3CN and NaBH (OAc) 3. A compound of formula I can also be obtained by treatment of a precursor, which instead of hydrogen atoms contains one or more reducible groups and / or one or more additional CC and / or CN bonds, with a reducing agent, preferably at temperatures between -80 and + 250 ° C and in the presence of at least one inert solvent. The reducible groups (and replaceable by hydrogen) are, in particular, the oxygen of a carbonyl, hydroxyl, arylsulfonyloxy (eg p-toluenesulfonyloxy), N-benzenesulfonyl, N-benzyl or O-benzyl group. In principle, compounds containing only one of the additional groups or bonds mentioned or compounds containing two or more mentioned groups or additional adjacent bonds can be transformed into a compound of formula I by reduction, which also allows simultaneously reducing substituents of the Group I that are present in the starting compound. This is preferably carried out with nascent hydrogen or complex metal hydrides, also by reduction of Wolff-kishner or by reduction with hydrogen gas and a transition metal as a catalyst.

If nascent hydrogen is used as the reducing agent, it can be generated, for example, by treating metals with weak acids or bases. It is thus possible, for example, to use a mixture of zinc with an alkali metal hydroxide or a mixture of iron with acetic acid. It is also suitable to employ sodium or other alkali metal dissolved in an alcohol such as ethanol, isopropanol, butanol, amyl or isoamyl alcohol or phenol. An aluminum and nickel alloy in alkaline and aqueous solution can also be used, possibly adding ethanol. To generate the nascent hydrogen, the amalgam of sodium or aluminum in hydroalcoholic solution or in aqueous solution is also suitable. The reaction can also be carried out in heterogeneous phase, for which it is advisable to use an aqueous phase and a benzene or toluene phase. As the reducing agent, complex metal hydrides such as LiAlH4 are also particularly suitable., NaBH4, diisobutylaluminum hydride or NaAl- (0CH2CH20CH3) 2H2 and diborane. If desired, catalysts such as BF3, A1C13 or LiBr can be added. Suitable solvents for this purpose are, in particular, ethers such as diethyl ether, di-n-butyl ether, THF, dioxane, diglyme or 1,2-dimethoxyethane, and hydrocarbons such as benzene. Suitable solvents for the reduction with NaBH 4 are above all alcohols such as methanol or ethanol, then water and aqueous alcohols. The reduction by these methods is preferably carried out at temperatures between -80 and +150 ° C, in particular between approximately 0 and 100 ° C. In addition, certain reductions can be carried out with H2 gas and the catalytic action of transition metals such as, for example, Ni-Raney or Pd. In this way, groups such as Cl, Br, I, SH, or, in some cases, also OH, can be replaced by hydrogen. The nitro groups can also be transformed into NH2 groups by catalytic hydrogenation with Pd / H2 in methanol. Compounds which correspond to formula I, but which in the place of one or more H atoms contain one or more solvolizable groups, can be solvolized, in particular hydrolysed, to give compounds of formula I. A compound of formula I can also be be converted to another compound of formula I using known methods.

The compounds of formula I, wherein R 1 represents a moiety substituted with CONH 2, CONHA or C0NA 2, can be obtained by derivatization of the correspondingly substituted compounds of formula I and partial hydrolysis. It is also possible to hydrolyze to acids the compounds of formula I substituted with cyano groups, then to convert the acids into amides by reaction with primary or secondary amines. It is preferred to react the free carboxylic acid with the amine under the conditions of a peptide synthesis. This reaction is preferably carried out in the presence of a dehydrating agent, for example a carbodiimide such as dicyclohexylcarbodiimide or N- (3-dimethylamino-propyl) -N-ethylcarbodiimide, then also propanephosphonic anhydride (cf. Angew. 9_2, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon such as dichloromethane, an ether such as THF or dioxane, an amide such as DMF or dimethylacetamide, a nitrile such as acetonitrile, at temperatures between about -10 and 40 ° C, preferably between 0 and 30 ° C. In place of the acid or the amide, reactive derivatives of these compounds can also be used, for example, those derivatives in which the reactive groups are temporarily blocked with protecting groups. The acids can also be used in the form of their activated esters which are conveniently formed in si t u, for example, by the addition of 1-hydroxybenzotriazole or N-hydroxysuccinimide. In this manner, for example, indole radicals substituted with a cyano group can also be hydrolyzed to obtain carboxyindole or carboxamido-indole moieties. On the contrary, it is also particularly convenient to obtain the nitriles from the amides by separating water, for example, with trichloroacetyl chloride / Et3N [Synthesis (2), 184 (1985)] or with P0C13 (J. Org. Chem. 2_6, 1003 (1061)). A base of formula I can be converted into its corresponding salt by the addition of an acid. Acids which form acceptable salts from the physiological point of view are suitable for this reaction. Therefore, inorganic acids such as, for example, sulfuric acid, hydrocides such as hydrochloric or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid and sulfamic acid, and also organic acids can be used. in particular the mono- or polybasic aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic, sulfonic or sulfuric acids such as formic, acetic, propionic, pivalic, diethylacetic, malonic, succinic, pimelic, fumaric, maleic, lactic, tartaric, malic acid , banzo, salicylic, 2-phenylpropionic, citric, gluconic, ascorbic, nicotinic, isonicotinic, methanesulfonic or ethanesulfonic, ethanedisulfonic, 2-hydroxyethanesulfonic, benzenesulfonic, p-toluenesulfonic, naphthalene monosulfonic, naphthalenedisulfonic and lauryl sulfuric. If desired, the bases of formula I may also be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, or sodium or potassium carbonate, provided that no other acidic groups exist. the molecule. In cases where the compounds of formula I have free acid groups, the formation of the salt can also be carried out by treatment with bases. Suitable bases are the alkali metal and alkaline earth metal hydroxides, or the organic bases in the form of primary, secondary or tertiary amines.

The invention also relates to the use of the compounds of formula I and their physiologically acceptable salts to obtain pharmaceutical preparations, in particular by a non-chemical route. For these purposes, the compounds can be brought into a suitable dosage form together with at least one excipient or solid auxiliary product, liquid and / or semi-liquid and, optionally, in combination with one or more additional active substances. Another object of the invention are compositions, in particular pharmaceutical preparations, containing at least one compound of general formula I and / or one of its physiologically acceptable salts. These preparations can be used in medicine and veterinary medicine as medicines. Among the excipients there may be mentioned organic or inorganic substances which are suitable for enteral (for example, oral), parenteral or topical administration and which do not react with the new compounds. Examples of these excipients are water, vegetable oils, benzylic alcohols, polyethylene glycols, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petrolatum. For enteral administration, in particular, tablets, dragees, capsules, syrups, juices, drops or suppositories are used, for parenteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions or implants, and for topical application, ointments, creams and powders. The new compounds can also be lyophilized and the resulting lyophilized products can be used, for example, for the preparation of injectable preparations. The preparations mentioned can be sterilized and / or contain auxiliary substances such as lubricants, preservatives,. stabilizers and / or wetting agents, emulsifying agents, salts for influencing the osmotic pressure, pH regulating substances, dyes, taste-correcting substances and / or flavors. If desired, they may also contain one or more additional active substances, such as, for example, one or several vitamins. The compounds of formula I and their physiologically acceptable salts can be used for the therapeutic treatment of the animal or human body and to combat diseases. They are suitable for treating central nervous system disorders such as tension states, depressions, panic attacks, schizophrenia, gastrointestinal disorders, stomach discomforts, tardive dyskinesia, parkinsonism and / or psychosis, and treat side effects in the treatment of hypertension (eg with a-methyldopa). the compounds can also be used in endocrinology and gynecology, for example, for the therapeutic treatment of acromegaly, hypogonadism, secondary amenorrhea, premenstrual syndrome and unwanted puerperal lactation, and also for the prophylaxis and therapy of brain alterations (for example, migraine), mainly in geriatrics and similar to that of certain ergot alkaloids. In particular, it is preferred to use these compounds as therapeutic substances intended to combat the sequelae of a cerebral infarction (cerebral apoplexy) such as apoplectic attack and cerebral ischemia, and to treat cerebral and spinal cord injuries. However, these compounds are particularly suitable to be used as anxiolytic active substances, antidepressants, antipsychotics and / or to exert a positive influence on obsessive behaviors (OCD), sleep disorders, tardive dyskinesia, disorders in learning. , senile disorders of memory, eating disorders such as bulimia and / or disorders of sexual function. For these treatments, the substances of formula I of the invention are generally administered analogously to known and commercial preparations (for example, bromocriptine, dihydroergocornine), preferably in doses between approximately 0.2 and 500 mg , in particular between 0.2 and 50 mg per dosage unit. The daily dose is preferably comprised between about 0.001 and 10 mg / kg of body weight. The lower doses are between 0.2 and 500 mg, in particular between 0.2 and 50 mg per dosage unit. The lower doses (approximately 0.2 to 1 mg per dosage unit, approximately 0.001 to 0.005 mg / kg body weight) are intended, in particular, for use as an anti-migraine agent; for the other indications, the doses comprised between 10 and 50 mg per dosage unit are preferred. However, the particular dose for each patient depends on a wide variety of factors, for example, the effectiveness of the particular compound used, age, body weight, general state of health, sex, diet , the timing and method of administration, the rate of excretion, the combination of medications and the severity of the particular disease to which the therapy is applied. Oral administration is preferred. All temperatures indicated in this text are given in ° C. In the examples that follow, the expression "is worked or treated in the usual manner" means the following: if necessary water is added, if necessary the pH is adjusted to values between 2 and 10, according to the constitution of the The final product is extracted with ethyl acetate or dichloromethane, the phases are separated, the organic phase is dried over sodium sulfate, filtered, the filtrate is concentrated by evaporation and purified by chromatography on silica gel and / or by recrystallization. . the Rf values were determined by thin layer chromatography on silica gel. The values of M + + 1 were determined by FAB-MS (rapid atom bombardment - mass spectrometry).

Example 1 0.79 g (0.003 mol) of 4- (2-oxo-2H-l-benzopyran-4-yl) -piperazine [obtained, for example, by reaction of N, N-bis- (2-chloroe. useful) -amine with 4-amino-2-oxo-2H-l-benzopyran] and 0.80 g (0.003 mol) of 3- (-chlorobutil) -5-cyano-indole [which can be prepared by reduction of 3- ( 4-chlorobutanoyl) -indol-5-carbonitrile] in 100 ml of acetonitrile, 0.50 ml (0.004 mol) of triethylamine and 1.20 ml (0.007 mol) of ethyldiisopropylamine are added and the mixture is stirred overnight in a steam bath. After working the reaction mixture in a usual manner, 3- is obtained. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indol-5-carbonitrile, dihydrochloride, m.p. 284-285 °. The following compounds are obtained analogously: 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indol, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -5-fluoro-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -5-chloro-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -l-piperazinyl] -butyl} -5-methoxy-indole, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-5-ethoxy-indole, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-indol-5-carboxylic acid methyl, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-6-fluoro-indole, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-6-chloro-indole, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-6-methoxy-indole, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-6-ethoxy-indo1, 3-. { 4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-indole-6-carboxylic acid methyl, 3-. { 4- (2-Oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] butyl-indole-6-carbonitrile.

EXAMPLE 2 A mixture of 8.3 g (0.031 mole) of 4- (2-oxo-2H-1-benzopyran-6-yl) -piperazine hydrochloride (prepared as a mixture) is stirred overnight in a 120-130 ° bath. analogously to that of example 1), 7.70 g (0.033 mol) of 3- (4-chlorobutyl) -5-cyano-indole (prepared analogously to that of example 1), 6.7 g (0.066 mol) of triethylamine, 11.3 ml (0.066 moles) of ethyldiisopropylamine and 55 ml of l-methyl-2-pyrrolidone. Then the suspension is stirred inside 4 1 of ice water and after stirring for a long time, 3- is obtained. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} crystalline -indol-5-carbonitrile, m.p. 135-137 °, as dihydrochloride, m.p. 282-284 °. The following compounds are obtained analogously: 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indol, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carbonitrile, monohydrochloride, m.p. 287-290 °, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -5-methoxy-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -5-ethoxy-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} - 6-methoxy-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -6-ethoxy-indo1, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carbonitrile.

Example 3 A mixture of 5.10 g (0.017 mole) of 4- (5-fluoro-indol-3-yl) -butyl methanesulfonate [obtained by the reaction of 4- (5-fluoro-indol-3-yl) is reacted) -butanol (obtained by reduction with aluminum hydride and lithium of 4- (5-fluoro-indol-3-yl) -butanoic acid, which can be synthesized in a manner analogous to that of a Japp-Klingemann reaction, in THF) with methanesulfonyl chloride], 4.0 g (0.015 mol) of 4- (2-oxo-2H-2H-l-benzopyran-6-yl) -piperazine, hydrochloride (obtained analogously to that of example 1) , 200 ml of acetonitrile and 10.0 ml of triethylamine by stirring for 30 hours in a steam bath. After working the reaction mixture in a usual manner, 3- is obtained. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -5-fluoro-indole, hydrochloride, m.p. 293-295 °. The following compounds are obtained analogously: 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] butyl} -5-chloro-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] butyl} -6-fluoro-indole, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] butyl} -6-chloro-indole, 3-. { 4- [4- (7-hydroxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indol, 3-. { 4- [4- (7-hydroxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -5-fluoro-indole, 3-. { 4- [4- (7-hydroxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -6-fluoro-indole, 3-. { 4- [4- (7-hydroxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -5-chloro-indole, 3-. { 4- [4- (7-hydroxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -6-chloro-indole.

Example 4 A mixture of 0.0098 mole of 4- (5-methoxycarbonyl-indol-3-yl) -butyl methanesulfonate (prepared analogously to Example 3) and 0.0097 mole of methanesulfonate is heated for 96 hours in a steam bath. - (2-oxo-2H-l-benzopyran-6-yl) -piperazine in acetonitrile. The reaction mixture is worked up and purified in the usual manner. In this way you get 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-methyl carboxylate. The following compounds are obtained analogously: 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-methyl carboxylate, 3- . { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indol-6-carboxylic acid methyl ester, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-cyano-2-oxo-2 H -1-be-zopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid methyl.

Example 5 For 30 minutes they are heated to boiling 1. 8 g of 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid methyl ester with 100 ml of 2N ethanolic KOH. The reaction mixture is then worked up in the usual manner and the 3- acid is obtained. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid. In an analogous way, it is obtained: 3- acid. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl] -butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-5-carboxylic acid, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-5- carboxylic acid, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid,. 3- acid. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-6-yl) -l-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-6-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-methyl-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-methoxy-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl-butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-fluoro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-chloro-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid, 3-. { 4- [4- (7-cyano-2-oxo-2H-l-benzopyran-4-yl) -1-piperazinyl] -butyl} -indole-6-carboxylic acid. The following examples refer to pharmaceutical preparations: Example A: vials for injections The pH of a solution of 100 g of an active substance of formula I and 5 g of disodium hydrogen phosphate in 3 1 of bidistilled water is adjusted to 6.5 with 2 N hydrochloric acid, then filtered under sterile conditions , fill the jars with the solution, lyophilize and close the bottles under sterile conditions. Each bottle for injection contains 5 mg of the active substance.

Example B: suppositories A mixture composed of 20 g of an active substance of formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted, then the melt is poured into the molds and allowed to cool. Each suppository contains 20 mg of active substance.

Example C: solution A solution is prepared with 1 g of an active substance of formula I, 9.38 g of NaH2P04 x 2H20, 28.48 g of NaH2P04 x 12 H20, 0.1 g of benzalkonium chloride and 940 ml of bidistilled water. The pH is adjusted to 6.8, brought to 1 1 volume and sterilized by irradiation. This solution can be used in the form of eye drops.

Example D: ointment Under aseptic conditions 500 mg 'of an active substance of formula I are mixed with 99.5 g of Vaseline.

Example E: Tablets A mixture composed of 1 kg of an active substance of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the form of tablets, so such that each tablet contains 10 mg of the active substance.

Example F: Dragees The tablets are formed analogously to that described in Example E and are then coated in a usual manner with a bath of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsules With 2 kg of an active substance of formula I, hard gelatine capsules are filled, so that each capsule contains 20 mg of the active substance.

Example H: ampoules The ampoules are filled with a solution of 1 kg of an active substance of formula I in 60 1 of bidistilled water, then lyophilised and closed under sterile conditions. Each ampoule contains 10 mg of the active substance. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (7)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. Compounds of formula I characterized in that R1 represents an indole-3-yl residue unsubstituted or mono or disubstituted with Hal, CN, A, AO, OH, C0NH2, CONHA, CONA2, COOH, COOA, CH2OH, CH2OA, CH2NH2, CH2NHA and / or CH2NA2 , R2 represents 2-oxo-2H-l-benzopyran-6-yl or 2-oxo-2H-benzopyran-4-yl unsubstituted or mono- or di-substituted with A, AO, OH, Hal, CN, N02, NH2, NHA , NA2, COA, C0NH2, CONHA, CONA2, CH2OH, CH2OA, CH2NH2, CH2NHA, CH2NA2, COOH and / or COOA, Hal represents F, Cl, Br or I, A represents straight or branched chain alkyl with 1 to 10 atoms of C and which may be substituted with 1 to 5 atoms of F and / or Cl, or cycloalkyl of 3 to 10 C atoms, m is 2, 3 or 4, and their salts are acceptable from a physiological point of view.

2. Compounds according to claim 1, characterized in that they are: a) 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -indole-5-carbonitrile; b) 3-. { 4- [4- (2-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -5-fluoro-indole; c) 3-. { 4- [4- (2-oxo-2H-l-benzopyran-4-yl) -1- piperazinyl] -butyl} -indol-5-carbonitrile; d) 3-. { 4- [4- (7-hydroxy-oxo-2H-l-benzopyran-6-yl) -1- piperazinyl] -butyl} -i dol-5-carbonitrile; and the physiologically acceptable salts of these compounds.

3. Process for preparing the piperazine derivatives of formula I, according to claim 1, and their salts, characterized in that a compound of formula II is reacted HN N-FT ii wherein R2 has the indicated meaning, with a compound of formula III R1- (CH2) m- (CO) x-L III wherein L represents Cl, Br, I, OH, OCOA, OCOPh, OS02A, 0S02Ar, where Ar is phenyl or tolyl and A is alkyl, or represents another esterified and reactive OH group or leaving group easily replaceable by a nucleophile and R1, myk they have the meaning indicated above, or a compound of formula IV is reacted by reductive amination. wherein R1 and m have the meaning indicated above, with a compound of formula II, or because a compound is treated which responds to formula I, but which in the place of one or more hydrogen atoms contains one or more reducible groups and / or one or more additional CC and / or CN bonds, with a reducing agent, or by treating a compound that responds to formula I, but which in the place of one or several hydrogen atoms contains one or more solvolizable groups, with a solvolizing agent, and / or because a radical R1 and / or R2 is optionally converted to another radical R1 and / or R2, for example, by cleaving an OA group to form an OH group and / or derivatizing a CN group, COOH or COOA and / or by alkylating, for example, a primary or secondary nitrogen atom and / or converting a base or an acid of formula I, thus obtained, into one of its salts by treatment with an acid or one base.

4. Process for obtaining pharmaceutical preparations, characterized in that a compound of formula I and / or one of its physiologically acceptable salts is brought into a suitable dosage form, together with at least one excipient or auxiliary solid, liquid or semi-liquid product and, optionally, in combination with one or more different active substances.

5. Pharmaceutical preparation, characterized in that it contains at least one compound of general formula I and / or one of its physiologically acceptable salts.

6. Use of the compounds of formula I, according to claim 1, or of their physiologically acceptable salts for preparing a medicament.

7. Use of the compounds of formula I, according to claim 1, or of their physiologically acceptable salts to combat diseases.